Vaccine Provides Strong Protection against HIV-like Infection in Monkeys. 6/1/11

Plans underway for early-stage human studies of vaccine candidates

AIDSMap

A new vaccine approach provided monkeys with a high level of protection against a virulent form of SIV, the monkey equivalent of HIV. Vaccine researchers say the findings are promising, and provide important pointers on how to design an HIV vaccine.

In particular the study found that two potential vaccine regimens reduced the per-exposure risk of infection by an estimated 80-83%.

The study was a collaboration between Crucell Holland B.V., the Beth Israel Deaconess Medical Center and Ragon Institute of MGH, MIT and Harvard, and the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research. It was funded by the Ragon Institute, the US Military HIV Research Program and the US National Institute of Allergy and Infectious Disease.

The study used a vaccine approach called prime-boost, in which monkeys received a “priming” dosing regimen of one vaccine, followed by a booster shot of a different vaccine 24 weeks later.

The study also tested the impact of different vectors, the harmless viruses which deliver the non-infectious sequences of HIV or SIV genes that are designed to stimulate an immune response to the virus. Vectors are chosen on the basis of their suitability for delivering gene sequences to cells, or for their ability to provoke strong immune responses. (See Types of HIV vaccine for further information).

The study tested a number of different combinations of vaccines:

Each vaccine combination was given to eight animals.

The adenovirus vector has been developed by Crucell, a Dutch company that forms part of the Johnson & Johnson group, and uses adenovirus type 26, which is not commonly found in humans. A previous adenovirus-vectored vaccine, using  the Ad5 serotype that is widespread in humans, was tested in the STEP trial, and may have contributed to the greater risk of infection observed in participants with higher levels of immunity to Ad5.

Six months after the boost immunisation monkeys were exposed to a rectal inoculation using a type of SIV that was genetically different from the SIV genes contained in the experimental vaccines in order to test their potential for preventing infection with a virus of a different genetic profile.

This virus was also chosen for its ability to evade neutralisation by antibodies.

This stringent approach was designed to set a high bar for success.

Three-quarters of the animals in the control group became infected after the first exposure to SIV, compared with less than a quarter of animals that received one of the vaccine combinations. Animals continued to receive regular exposures to SIV, and not all monkeys became infected, even after four challenges.

Animals that received the two vaccine combinations containing Ad26 proved particularly hard to infect. After three rounds of exposure, only 50% of animals that received the Ad26/MVA or MVA/Ad26 regimens had become infected, compared to a 50% infection rate after one round of exposure in the control group. This represented an 80-83% reduction in the per-exposure probability of infection, although the confidence intervals were fairly wide, due in part to the small number of animals studied (95% confidence intervals 0.05-0.57 and 0.06 – 0.063).

The Ad-26-containing regimens were also associated with significantly lower viral load setpoints in animals that did become infected. The point at which viral load stabilises after the early months of infection is a strong predictor of the subsequent risk, and speed, of HIV disease progression.

Two hundred and fifty days after infection animals immunised with an Ad26-containing regimen had mean viral load setpoints 2.32 log  (Ad26/MVA) and 1.08 log (MVA/Ad26) below those of animals in the control group (P=0.0037).

In addition three of the seven infected animals in the Ad26/MVA group rapidly demonstrated that their immune systems were controlling the virus to such an extent that they had sustained undetectable viral loads.

After analysing the immune system responses that were correlated with protection from infection, delayed infection or virological control after infection, the researchers have concluded:

Plans are now underway for early-stage human studies of vaccine candidates adapted from one of the most successful prime-boost combinations used in this study.

Effects of HIV on Malaria. Living with AIDS # 495. 10/11/11

People living with HIV and AIDS are at more risk of severe complications and even death should they contract malaria.

Health-e

With the summer season comes along excessive heat, rains and humidity. As a result, certain parts of the country like the northern parts of Limpopo, eastern Mpumalanga and northern KwaZulu-Natal, are likely to breed conditions for the development of malaria-causing mosquitoes. The parasites are particularly dangerous for all at this time of the year, but they can introduce even greater havoc in people with HIV, according to Professor John Frean, head of the Microbiology Division at the National Institutes for Communicable Diseases (NICD), in Johannesburg.

“It’s not surprising that there would be some influence of HIV on malaria because HIV affects the cellular immune system, which is very important in combating malaria”, Professor Frean says.

In South Africa, malaria is not endemic. It occurs seasonally from about September to May, with the peak periods being the months of January and February. Because of malaria being a seasonal disease, South Africans do not acquire any immunity to the parasitic infection as they are not exposed to it enough during a lifetime. Hence, when malaria strikes, it often has severe consequences.  

“We have to distinguish between two groups of people with malaria. Those who are what we call semi-immune… They’ve grown up in malaria-endemic areas… they’ve been exposed from an early age… They have a certain amount of resistance. One never develops absolute resistance to malaria, but they are able to tolerate the infection much better than the other group of patients who are people who have grown up in areas where malaria is not endemic. It may occur on a seasonal basis – what we call unstable malaria. Those individuals in unstable malaria areas are not semi-immune to malaria and they are more susceptible to the severe effects of malaria, and HIV places them at even greater risk”, explains Professor Frean.

“Children living in high transmission areas - with their first attack, may die – and a lot of children do. But repeated infections, with time - and these are very frequent infections - they will acquire some immunity so that by the time they are adolescents or young adults their malaria illness is usually very mild or even asymptomatic”, adds NICD Deputy Director, Professor Lucille Blumberg.   

But if one has HIV this semi-immunity becomes lost. 

“HIV does change that and people living in high transmission areas, who might have acquired some immunity, if they are HIV-infected they will present more commonly with clinical malaria rather than being asymptomatic, they may have a higher number of parasites and some people may be susceptible to more severe malaria”, says Blumberg.  

 “People with HIV who get malaria are liable to get more serious infections, more likely to become severe and complicated and have an increased risk of death, especially in areas where medical facilities are not that good or the high standard of care required to treat a patient with severe malaria is not present – intensive care units, for example”, Frean adds.    

But a compromised immune system is not the only risk factor. Professor Blumberg says people often don’t take malaria symptoms, which usually start with a fever, seriously. 

“I think, particularly for people in South Africa, we’ve noticed delays in seeking care for an acute illness with fever if you’re living in a malaria area – and that would be what we’d encourage because, especially, if they’re not on ARVs, other infections are quite common and they attribute it - the fever they’re having – to the usual HIV-associated infection and they don’t think about the malaria. I think you’re getting late presentation, delayed diagnosis and, because of that, an increased risk of complications and an increased risk of a fatal outcome”, she says.

Blumberg warns that it’s very important for people not to misinterpret the symptoms.       

“If you’re not living in a malaria area and aware of malaria, you may ignore that fever or you may think it’s flu. The symptoms over-lap. And if you look back on people who have died of malaria, often the first misdiagnosis was flu – fever, head-ache, cold shivers, hot sweats, muscle pain. It’s just like flu. And both the person affected and the health care worker may make that error. So, I think a high index of suspicion for malaria, especially during the season, in anybody who lives in a malaria area or has traveled to a malaria area is very important”, she says.

About 7 000 cases of malaria are recorded annually in the malaria-prone areas of South Africa. And about 40 – 80 people die as a result of the infection, with the majority of deaths occurring in people who have HIV.

The Unsung Revolution. 28/9/11

The decade’s most important development in HIV science has gone largely unnoticed in the South African media.

Health-e

For the first time in the thirty-year history of the global HIV epidemic, there is now conclusive evidence that initiating antiretroviral treatment at an earlier stage in disease progression can prevent HIV transmission as well as improve the health of people living with HIV.

The international study (referred to as ‘HPTN 052’), enrolled 1,763 sero-discordant couples, in which one partner was HIV-positive and the other HIV-negative. The study was conducted across seven countries and three continents (Africa, Asia and South America). Participants were assigned randomly into one of two groups. In the first group, HIV-positive partners received antiretroviral treatment at an earlier stage in their disease progression, when their CD4 count was between 350 – 550 cells/mm3. In the second group, HIV-positive partners received antiretroviral treatment at a later stage, when their CD4 counts had dropped below 250 cells/mm3, or they had experienced an AIDS-defining illness. Intensive counseling, including HIV prevention information, condoms and testing was provided to all participants for the course of the study.

A preliminary review of the study’s results by the data and safety monitoring board, an independent group of experts that advises study investigators, found that the benefits of early initiation of antiretroviral treatment were so conclusive that all participants in the study should be offered immediate antiretroviral treatment. HIV-positive partners on antiretroviral treatment had a 96% reduction in transmitting HIV to their HIV-negative partners if they started treatment earlier, at a CD4 count of between 350 – 500, compared to trial participants who initiated treatment at a CD4 count of 250 and below.

The study also found that participants who received antiretroviral treatment immediately experienced further clinical benefits compared to those in the deferred treatment arm. There was a significant reduction in their incidence of extrapulmonary tuberculosis – 17 cases among participants who had started antiretroviral treatment earlier versus 3 cases among participants who had initiated treatment later.

These ground-breaking results were presented at the recent International AIDS Society conference in Rome. The response of clinicians and activists was jubilant – with spontaneous celebrations breaking out in the corridors of the conference venue. Clinicians and scientists have long believed that antiretroviral treatment may reduce HIV transmission, with many HIV prevention programmes using antiretrovirals as a mainstay since the late 1990s. These include programmes to prevent the transmission of HIV from mother to child, and post-exposure prophylaxis interventions for rape survivors and healthcare workers to prevent HIV ‘sero-conversion’ after a potential infection.

Why is this study so important, and what are its implications for South Africa? The global financial crisis precipitated a backlash against funding for antiretroviral treatment programmes. Numerous major international donors have reduced their funding of antiretroviral treatment programmes in South Africa, partly because of a belief that the costs of antiretroviral treatment outweighs its benefits, and that scarce money for public health is better spent elsewhere. 

This thinking chimes with widespread, reactionary beliefs about the alleged harms of antiretroviral drugs. These include unfounded claims of how antiretroviral drugs benefit only those who take them, when in fact the drugs benefit societies at large through preventing new HIV infections and improving the health outcomes of those living with HIV (and, by extension, their families and communities).

Another misconception regarding antiretrovirals is that they help to spread HIV by extending the lifespan of those living with the virus. While it is true that antiretrovirals help to ensure that people with HIV live longer and healthier lives, because the drugs reduce the amount of virus in the blood, it becomes much more difficult for someone who is adhering to treatment and whose viral load has plummeted, to transmit HIV to their partners through unprotected sex.

Antoinette Goosen, the National Chairperson of the South African Association for Campus Health Services, explained that HIV-positive students who were initiated onto ART are counseled extensively to ensure that they understand the importance of adherence to treatment and of safe sex to prevent HIV transmission. Goosen stated: ‘Half of the patients that we initiated onto ART last year were at death’s door. Within a period of two months, it was like waving a magic wand over these people’s bodies and lives. We saw such a dramatic change in them, that I can never ever think that the price and cost of ARVs can outweigh their benefits. These were young people who would have died last year. They are now at the point of completing their courses, graduating, and looking forward to the future.’ 

Julialynne Walker, Director of Development and Information for the Population Council, believes that, with ART provision comes the responsibility for treatment education and for programmes that address the other reproductive health needs of people living with HIV. Walker stated: ‘The health system has to begin to develop family planning for HIV-positive or sero-discordant couples.’

Despite common misconceptions about antiretrovirals, fuelled partly by the false claims of previous high-ranking political officials, South Africa’s antiretroviral treatment programme expands daily. At present, over 1.4 million people have initiated antiretrovirals, making the programme one of the biggest public health initiatives in history.

In the last decade, over seven million people living with HIV across the globe have begun taking antiretroviral treatment. The potential number of HIV transmissions that may have been prevented as a result of this is enormous, and will hopefully be quantified by future modeling studies.

The recent scientific breakthrough, in the form of the HPTN052 trial, shows conclusively that antiretroviral treatment also prevents HIV infections. These results have already begun to influence South Africa’s response to the HIV epidemic. Deputy President Kgalema Motlanthe announced recently that access to antiretroviral treatment would be provided to all South Africans with a CD4 count of 350 and below in the public health sector. While other government officials have alleged that this commitment to expanding antiretroviral access is unaffordable, sensitive costing studies have proven otherwise. One such study indicated that raising the CD4 count at which patients in South Africa initiated antiretroviral treatment to 350, in line with the recommendations of the World Health Organisation, would lead to a major net savings. [Hontelez JAC, de Vlas SJ, Tanser F, Bakker R, Barnighausen T, et al. (2011) This costing study concluded that, ‘Apart from the benefits associated with many life-years saved, a modest frontloading appears to lead to net savings within a limited time-horizon’. It recommended that South Africa should aim to expand its HIV treatment programme rapidly to provide treatment to all people living with HIV at a higher CD4 count of 350.

Professor Nicoli Nattrass, an economist and the director of the AIDS and Society Research Unit at the University of Cape Town, agrees that the long-term cost benefits of earlier antiretroviral initiation must be factored into government’s response: ‘It is crucial that government looks beyond the immediate budget cycle and considers health care costs over the longer term”, she stated. “It makes no sense to save money now by denying people early ARV treatment when this will actually save the government money over the longer term. Early treatment will reduce new HIV infections and prevent people becoming sick with AIDS.  This will save the government huge amounts of money over the next three to ten years.”

The results of the HPTN 052 trial make it more urgent than ever for governments in South Africa and the region to scale-up antiretroviral treatment programmes. The moral imperative to provide treatment is now supported by clinical, epidemiological and fiscal evidence. For the first time in the history of HIV, science has shown that it is possible to end the HIV pandemic through timely, universal provision of treatment. By starting people onto antiretroviral treatment at an earlier stage in their disease progression with HIV, government has grasped a vital opportunity to prevent new HIV infections as well as reducing HIV-related illness and death.

Weird Science Helping Bid to Defeat Virus. 23/9/11

Three recent developments in HIV research

Nairobi - Computer gamers, glow-in-the-dark cats and neutralizing viruses sound like the stuff of science fiction but they may be the key to eliminating HIV.

More than 33 million people are infected with HIV globally, and while combination antiretroviral therapy is enabling people to have near-normal life spans, a cure has so far evaded researchers.

IRIN/PlusNews lists three recent developments in HIV research:

Computer gamers - The authors of a recent study published in the journal, Nature Structural & Molecular Biology, say they challenged players of a computer game known as Foldit - where gamers “fold” proteins in order to understand more about their structure - to produce accurate models of the protein, Mason-Pfizer Monkey Virus, an enzyme that is vital in the development of a simian-borne virus similar to HIV.

Proteins are critical for the virus to replicate inside the body; the more scientists understand about the structure of proteins, the better equipped they are to design drugs to fight disease-related proteins.

In the space of the three-week competition, the gamers were able to unlock the structure of M-PMV, something scientists have struggled with for years; scientists from the university say the discovery provides opportunities for the design of anti-HIV drugs.

Foldit was developed in 2008 by the University of Washington.

“Glow in the dark” cats - Cats are vulnerable to Feline Immunodeficiency Virus (FIV), which is similar to HIV; the journal Nature recently published research by US scientists showing that cells from cats carrying a particular gene - rhesus macaque TRIMCyp - resisted the replication of FIV.

The eggs that produced the cats had the green fluorescent protein - which occurs naturally in jellyfish and fluoresces under certain light - inserted; it enables easy identification of the altered genes.

Scientists say that if the protective effect of the gene is proven by further research, it would be useful in developing similar techniques to reduce the replication of HIV in humans.

Disarming the virus - By removing cholesterol from the HI virus membrane, US and European scientists rendered the virus incapable of damaging the immune system. Cholesterol is important in maintaining the integrity of the HIV envelope and allowing HIV-cell interaction. The research was published in September in the journal, Blood.

In the human body, a subset of immune cells called plasmacytoid dendritic cells (pDCs) recognize HIV quickly and produce signalling molecules called interferons, which activate various processes that are initially helpful, but if active for too long, damage the immune system.

The scientists, from Imperial College London, Johns Hopkins University, the University of Milan and Innsbruck University, found that once cholesterol was removed from the HIV envelope, it no longer activated pDCs. Instead, T-cells - critical to the immune response - were able fight the virus more effectively.

The scientists now plan to investigate the possibility of transforming their method of disarming the virus into a vaccine.

Scientists to 'Disarm' AIDS Virus. 20/9/11

Chlestrol in virus membrane may be key.

News 24

London - Scientists have found a way to prevent HIV from damaging the immune system and say their discovery may offer a new approach to developing a vaccine against Aids.

Researchers from the US and Europe working in laboratories on the human immunodeficiency virus (HIV) found it is unable to damage the immune system if cholesterol is removed from the virus's membrane.

"It's like an army that has lost its weapons but still has flags, so another army can recognise it and attack it," said Adriano Boasso of Imperial College London, who led the study.

The team now plans to investigate how to use this way of inactivating the virus and possibly develop it into a vaccine.

Usually when a person becomes infected with HIV, the body's innate immune response puts up an immediate defence.

But some researchers believe HIV causes the innate immune system to overreact. This weakens the immune system's next line of defence, known as the adaptive immune response.

Limited success

For this study - published on Monday in the journal Blood - Boasso's team removed cholesterol from the membrane around the virus and found that this stopped HIV from triggering the innate immune response. This in turn led to a stronger adaptive response, orchestrated by a type of immune cells called T cells.

Aids kills around 1.8 million people a year worldwide. An estimated 2.6 million people caught HIV in 2009, and 33.3 million people are living with the virus.

Major producers of current HIV drugs include Gilead Bristol Myers Squibb , Merck , Pfizer and GlaxoSmithKline .

Scientists from companies, non-profits and governments around the world have been trying for many years to make a vaccine against HIV but have so far had only limited success.

A 2009 study in Thailand involving 16 000 volunteers showed for the first time that a vaccine could prevent HIV infection in a small number of people, but since the efficacy was only around 30% researchers were forced back to the drawing board.

An American team working on an experimental HIV vaccine said in May that it helped monkeys with a form of the Aids virus control the infection for more than a year, suggesting it may lead to a vaccine for people.

HIV is spread in many ways - during sex, on needles shared by drug users, in breast milk and in blood - so there is no single easy way to prevent infection. The virus also mutates quickly and can hide from the immune system, and attacks the very cells sent to battle it.

Tricky

"HIV is very sneaky," Boasso said in a statement. "It evades the host's defences by triggering overblown responses that damage the immune system. It's like revving your car in first gear for too long - eventually the engine blows out.

He said this may be why developing a vaccine has proven so tricky.

"Most vaccines prime the adaptive response to recognise the invader, but it's hard for this to work if the virus triggers other mechanisms that weaken the adaptive response."

HIV takes its membrane from the cell that it infects, the researchers explained in their study. This membrane contains cholesterol, which helps keep it fluid and enables it to interact with particular types of cell.

 

Antibody Trawl helps HIV Vaccine Search. 17/8/11

Discovery of 17 potent antibodies opens up valuable pathways in the search for an AIDS vaccine.

Paris - Researchers into HIV said they had identified 17 potent antibodies whose discovery opened up valuable pathways in the search for an Aids vaccine.

Antibodies are the foot soldiers in the immune system, latching onto viral or microbial intruders and tagging them for destruction by specialised "killer" cells.

Priming antibodies to recognise pathogens is a textbook method in vaccines, although it has proven agonisingly hard in the case of the human immunodeficiency virus (HIV) which causes Aids.

The new "broadly neutralising" antibodies are the biggest single haul so far and also many times more potent than those found previously, the scientists report in Thursday's issue of the British journal Nature.

"Most antiviral vaccines depend on stimulating the antibody response to work effectively," said Dennis Burton of the Scripps Research Institute in La Jolla, California.

"Because of HIV’s remarkable variability, an effective HIV vaccine will probably have to elicit broadly neutralising antibodies. This is why we expect that these new antibodies will prove to be valuable assets to the field of Aids vaccine research.

The International Aids Vaccine Initiative (IAVI), a US NGO that sponsored the search, said the quest for HIV-neutralising antibodies was "perhaps the greatest challenge" facing vaccine engineers.

The 17 antibodies were isolated from four individuals with HIV, an achievement similar to looking for a needle in a haystack as only a very small number of people produce these powerful molecules.

Aids has claimed some 30 million lives since the disease came to public notice in 1981.

Around 34 million people today are infected with HIV, according to UN estimates.

New Math in HIV Fight. 21/6/11

Statistical Method Evolves From Physics to Wall Street to Battle Against AIDS

The Wall Street Journal

Scientists using a powerful mathematical tool previously applied to the stock market have identified an Achilles heel in HIV that could be a prime target for AIDS vaccines or drugs.

The research adds weight to a provocative hypothesis—that an HIV vaccine should avoid a broadside attack and instead home in on a few targets. Indeed, there is a rare group of patients who naturally control HIV without medication, and these "elite controllers" most often assail the virus at precisely this vulnerable area.

"This is a wonderful piece of science, and it helps us understand why the elite controllers keep HIV under control," said Nobel laureate David Baltimore. Bette Korber, an expert on HIV mutation at the Los Alamos National Laboratory, said the study added "an elegant analytical strategy" to HIV vaccine research.

"What would be very cool is if they could apply it to hepatitis C or other viruses that are huge pathogens—Ebola virus, Marburg virus," said Mark Yeager, chair of the physiology department at the University of Virginia School of Medicine. "The hope would be there would be predictive power in this approach." Drs. Baltimore, Korber and Yeager weren't involved in the new research.

One of the most vexing problems in HIV research is the virus's extreme mutability. But the researchers found that there are some HIV sectors, or groups of amino acids, that rarely make multiple mutations. Scientists generally believe that the virus needs to keep such regions intact. Targeting such sectors could trap HIV: If it mutated, it would disrupt its own internal machinery and sputter out. If it didn't mutate, it would lie defenseless against a drug or vaccine attack.

The study was conducted at the Ragon Institute, a joint enterprise of Massachusetts General Hospital, the Massachusetts Institute of Technology and Harvard University. The institute was founded in 2009 to convene diverse groups of scientists to work on HIV/AIDS and other diseases.

Two of the study's lead authors aren't biologists. Arup Chakraborty is a professor of chemistry and chemical engineering at MIT, though he has worked on immunology, and Vincent Dahirel is an assistant professor of chemistry at the Université Pierre et Marie Curie in Paris. They collaborated with Bruce Walker, a longtime HIV researcher who directs the Ragon Institute. Their work was published Monday in the Proceedings of the National Academy of Sciences.

To find the vulnerable sectors in HIV, Drs. Chakraborty and Dahirel reached back to a statistical method called random matrix theory, which has also been used to analyze the behavior of stocks. While stock market sectors are already well defined, the Ragon researchers didn't necessarily know what viral sectors they were looking for. Moreover, they wanted to take a fresh look at the virus.

So they defined the sectors purely mathematically, using random matrix theory to sift through most of HIV's genetic code for correlated mutations, without reference to previously known functions or structures of HIV. The segment that could tolerate the fewest multiple mutations was dubbed sector 3 on an HIV protein known as Gag.

Previous research by Dr. Yeager and others had shown that the capsid, or internal shell, of the virus has a honeycomb structure. Part of sector 3, it turns out, helps form the edges of the honeycomb. If the honeycomb suffered too many mutations, it wouldn't interlock, and the capsid would collapse.

For years, Dr. Walker had studied rare patients, about one in 300, who control HIV without taking drugs. He went back to see what part of the virus these "elite controllers" were attacking with their main immune-system assault. The most common target was sector 3.

Dr. Walker's team found that even immune systems that fail to control HIV often attack sector 3, but they tend to devote only a fraction of their resources against it, while wasting their main assault on parts of the virus that easily mutate to evade the attack. That suggested what the study's authors consider the paper's most important hypothesis: A vaccine shouldn't elicit a scattershot attack, but surgical strikes against sector 3 and similarly low-mutating regions of HIV.

"The hypothesis remains to be tested," said Dan Barouch, a Harvard professor of medicine and a colleague at the Ragon institute. He is planning to do just that, with monkeys. Others, such as Oxford professor Sir Andrew McMichael, are also testing it.

The Ragon team's research focused on one arm of the immune system—the so-called killer T-cells that attack other cells HIV has already infected. Many scientists believe a successful HIV vaccine will also require antibodies that attack a free-floating virus. Dr. Chakraborty is teaming up with Dennis Burton, an HIV antibody expert at the Scripps Research Institute in La Jolla, Calif., to apply random matrix theory to central problems in antibody-based vaccines.

Novel Vaccine did Not Protect Monkeys against Infection – But May have Cured them. 19/5/11

"Vaccine" produced infections characterised by an undetectable viral load.

AIDSMap

A novel vaccine using the common virus Cytomegalovirus (CMV) as the vector or container of proteins from the simian immunodeficiency virus (SIV) protected none of a group of 24 rhesus macaques from infection. But in 13 of the monkeys vaccinated, it did produce infections characterised by an undetectable viral load.

This profound viral suppression led to an apparent decline in the number of SIV-infected cells over a period of two years after infection to the point that SIV-infected cells were undetectable in 72% of monkeys with controlled viremia. Despite this, there was no apparent waning of immune responses to SIV in the all-important effector-memory CD8 and CD4 lymphocytes over this time in 12 of the 13 monkeys.

The researchers comment that their vaccine seems to have produced “an unprecedented level of SIV control and even the possibility of progressive clearance of SIV infection over time”.

The question now is how to make a safe analogue of this vaccine for use in humans.

The Vaccine

The vaccine tested enclosed SIV components within the shell of another virus which establishes an ongoing but non-pathogenic infection. In this case they used CMV, which is a ubiquitous infection in rhesus monkeys and is present in about 50% of humans. The vaccine, therefore, acted not as a new viral infection but as a ‘superinfection’ of a new variety of CMV.

In this experiment, 24 rhesus macaques were given the novel CMV-vector vaccine, which contained the viral proteins gag, nef, rev, tat, env and parts of the polymerase (pol) protein. Twelve of these animals were given two doses of the CMV vaccine. The other twelve were given one dose of the CMV vaccine and then one dose of a more conventional adenovirus-vector vaccine containing the gag, pol, env and nef SIV proteins.

The 24 CMV-vaccinated animals were compared with nine animals given the adenovirus-vector vaccine alone. All vaccinated animals were then challenged, 13.5 months after the first vaccination shot, by rectal introduction of a highly pathogenic SIV variant.

The course of infection was compared with 28 controls that were all unvaccinated but were challenged with SIV: eleven were challenged with SIV at the same time as the vaccinated animals, while the other 16 had been challenged previously.

The Results

The CMV vaccine did not work by protecting the animals against infection and indeed every single one of the challenged animals was infected, with no statistical difference in the number of challenges need to establish infection.

Interestingly, one of the control animals displayed a delayed infection, maintaining an undetectable viral load despite testing antibody-positive for SIV for the first 105 days. After this, however, SIV suddenly appeared in the blood and soon established itself at normal levels, and the subsequent course of infection was similar to that in the other controls.

However, in just over half (13) of the CMV-vaccinated animals, the subsequent infection resembled those seen in ‘elite controllers’: after an initial spike of virus in the blood, they quickly achieved an almost complete control over their virus, maintaining viral loads under 30 copies/ml with occasional ‘blips’, usually to no more than 1000 copies/ml. The frequency of blips declined after week 30 post-infection from 1.5 blips per ten-week period to 0.1 per ten weeks, and then stayed at that frequency for the remainder of the 700-day follow-up period.

Immune responses in CD8 T-cells to the SIV gag and pol viruses remained strong throughout the follow-up period on CMV-vaccinated animals. In contrast, responses to an SIV protein that was not contained in the vaccine, the vif protein, while starting out at the same levels, declined to 10% of its initial level over the 700 days.  

The researchers hypothesised that this response to vif – which must be caused by the monkeys’ natural response to SIV – might be declining over time because the number of cells infected with SIV was declining.

This proved to be the case: after sacrificing four vaccinated animals, they tried to find cell-associated viral DNA in cells taken from the gut, lymph nodes and other tissues and found none in 72% of the animals. Excitingly, the levels of cell-associated DNA seen were almost indistinguishable from the proportion of ‘false positive’ DNA results seen in an uninfected animal and far lower – in the order of one DNA copy per 100 million cells – than the levels seen in two animals that had achieved long-term viral control in two previous vaccination experiments (about one DNA copy per half a million cells).

In the nine animals given the more conventional adenovirus vaccine, none achieved an undetectable viral load, but they did initially display a lower viral load that the control animals. However, their viral load eventually returned to normal levels.

Possible Significance

What is different about the CMV-based vaccine? Vaccines using viral vectors and ‘fake viruses’ are now almost commonplace. However, previous vaccines using viruses such as adenovirus have produced inconsistent results in animals and in humans, the only large efficacy trial using a viral vector alone, the STEP trial, may actually have increased some people’s vulnerability to HIV.  The more successful RV144 trial used another viral vector but the vaccine’s (rather weak) efficacy appeared to be generated by an antibody response to the other vaccine component, not to the viral vector.

The CMV vaccine stimulated immunity in a different group of T-cells. Previous viral vectors have stimulated immunity in the central memory T-cells that mainly dwell in sites like the lymph nodes. This vaccine however mainly stimulated immunity amongst the effector-memory T-cells that patrol the mucous membranes. The researchers hypothesise that the vaccine is able to interrupt the process of infection at an earlier stage, before the SIV has travelled to the lymph nodes and established a fully-productive infection.  

However, the researchers emphasised that there is a lot they still do not understand about the immune response seen to the CMV vaccine, exactly why it produced such a powerful response and, crucially, what distinguished the 13 monkeys who responded from the eleven who did not.

Vaccine researchers welcomed the study, but said that it might be difficult to manufacture a version of he vaccine that was safe to use in human studies, given that CMV can cause a number if significant illnesses, especially in people with AIDS and compromised immunity.

Professor Sir Andrew MacMichael of Oxford University told the BBC: "CMV is not totally benign, it does cause a number of diseases. If you're giving people something you're not going to be able to get rid of should it cause problems, then that's quite a difficult risk to manage."

Lead investigator Louis Picker, of the Vaccine and Gene Therapy Institute in Oregon, said in reply that 99% of people in sub-Saharan Africa are already infected with CMV. He said: "We know a lot about it and it's mostly non-pathogenic, except in vulnerable populations like pregnant women." He added that his team were now looking to create a vaccine that had the same immune activity with a weakened version of CMV that could not cause harmful infection.

Reference

Hansen SG et al. Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature, early online publication, doi:10.1038/nature10003. May 2011.

Zinc Finger Gene Therapy Produces HIV-resistant CD4 T-cells. 1/3/11

HIV resistant CD4 cell potential first step toward achieving a "functional cure"

AIDSMap

'Sleepy' Immune System Might Fight HIV. 16/2/11

A Manitoba AIDS scientist, who has spent 25 years trying to unlock the mystery of HIV-resistant sex workers in Kenya, says a reduced immune system might actually be the best defence against the disease.

This insight, if proven, could turn billions of dollars in global HIV vaccine research on its head.

And Dr. Frank Plummer and his research team hope their discovery will lead to the creation of an HIV vaccine gel for millions of women

When a person becomes infected with HIV, the virus goes after the immune system, breaking it down and infecting the cells.

So Plummer and his team studied what happens if an immune system doesn't fight back, doesn't give the virus anything to feed off.

The secret is trying to make an immune system more "sleepy" to HIV so the deadly virus never takes hold, said Plummer, scientific director of the National Microbiology Laboratory in Winnipeg.

The sex trade workers he's studied in Africa since 1985 do this naturally.

"One of the signature characteristics of these (women) is that they have what we call a quiescent immune, or if you like, a 'sleepy immune' system," Plummer told an audience attending a TedX Manitoba conference in Winnipeg on Tuesday.

Plummer and his team just won a five-year $680,000 federal grant to develop a microbicidal gel that will try to copy this protective effect.

The discovery is the result of years of tracking sex trade workers in Nairobi slums who have defied the odds and avoided HIV. Many of the women live in areas with 50 per cent HIV infection rates, where their sex work exposes their bodies to the virus many times a day, and over many years.

Salome Simon is an example. When she appeared in a CBC News The National documentary in 2006, she had been doing sex work uninfected for more than two decades.

"I was very happy to find out that I am resistant. I have seen many of my friends die, but I thank God that I don't have HIV," Simon told CBC News at the time through a translator.

Plummer believes women like her have a natural protection to HIV because their immune systems are so inactive in response to the virus.

Normally, a women's immune system reacts to HIV by sending in immune cells to counter the virus and stimulate inflammation in the vagina. This, unfortunately, provides avenues for viral infection.

But this wasn't happening in the Kenyan women.

"What we found is that [the sex trade workers] secrete these specific proteins which counter inflammation. This was counter-intuitive," says Dr. Adam Burgener, a University of Manitoba microbiologist who travels back and forth to Nairobi for the research.

"We would've thought there would be lots of inflammation and that they would mount a very strong response during sex work. But it's the opposite - they have a very subdued immune system," says Burgener.

Until now, people involved in vaccine development have focused on "jazzing up" the immune system, making it very active, said Plummer.

"And if our work is correct ... that may not be the best thing to do."

Pharmaceutical giant Merck found out the hard way. It invested heavily in a vaccine to boost immune systems, only to find out in its clinical trials in 2007 that the approach only made HIV infection worse.

So, the idea that a Manitoba-grown idea to conquer AIDS has researchers here, like Burgener, losing sleep.

"It's very exciting. I have difficulty sleeping on Sunday nights because I'm excited about the work week and what we have to accomplish in order to get into testing."

Math may Help Calculate Way to Find New Drugs for Diseases. 7/2/11

Formula to narrow their search to five promising drug candidates

Princeton

Using mathematical concepts, Princeton researchers have developed a method of discovering new drugs for a range of diseases by calculating which physical properties of biological molecules may predict their effectiveness as medicines.

The technique already has identified several potential new drugs that were shown to be effective for fighting strains of HIV by researchers at Johns Hopkins University.

"The power of this is that it's a general method," said Princeton chemical and biological engineering professor Christodoulos Floudas, who led the research team. "It has proven successful in finding potential peptides to fight HIV, but it should also be effective in searching for drugs for other diseases."

Floudas, the Stephen C. Macaleer '63 Professor in Engineering and Applied Science, and Princeton engineering doctoral student Meghan Bellows-Peterson collaborated on the study with researchers at the Johns Hopkins University School of Medicine. Their findings were reported in the Nov. 17, 2010, issue of Biophysical Journal.

The researchers' technique combines concepts from optimization theory, a field of mathematics that focuses on calculating the best option among a number of choices, with those of computational biology, which combines mathematics, statistics and computer science for biology research.

In the case of HIV, the challenge for the Princeton team was to find peptides -- the small chains of biologically active amino acids that are the basic building blocks of proteins -- that could stop the virus from infecting human cells.

"The Princeton researchers have a very sophisticated way of selecting peptides that will fit a particular binding site on an HIV virus," said collaborator Robert Siliciano, a professor of medicine at Johns Hopkins and a 1974 Princeton graduate, who specializes in the treatment of HIV. "It narrows the possibilities, and may reduce the amount of time and resources it takes to find new drugs."

Fuzeon (enfuvirtide), is a peptidic drug commonly given to HIV patients for whom first-line HIV medications have not proven fully effective. Fuzeon costs nearly $20,000 per year, and patients must take it regularly due to its short period of effectiveness in the body. The researchers hoped to find an alternative to Fuzeon by discovering new peptides that would be cheaper to produce and allow patients to take fewer and smaller doses.

Fuzeon is thought to inhibit HIV by attaching to the virus and disabling a structure used to penetrate the protective membrane of human cells.

"The actual mechanism for entering cells is still uncertain, but there is a lot of evidence that points to this certain structure on the virus," Bellows-Peterson said. "We used the available data on the proteins that form the structure to help us predict what kind of drug might be effective against the virus."

The researchers reasoned that a shorter peptide -- Fuzeon is 36 amino acids long-- would be cheaper to produce and would last longer in the body, since shorter molecules are less susceptible to breakdown. Such formulations also might allow for drugs that could be taken as a pill instead of an injection.

The researchers' biological sleuthing focused on the physical relationship between peptides and the HIV protein structure that Fuzeon targets. The team developed a formula based on statistical thermodynamics to predict whether a given peptide, based on its sequence of amino acids, was likely to bind with the protein that HIV uses for penetrating cells.

This tendency to bind stems from the peptide's free energy state, a physical property related to its shape, which would change if it attached to the HIV protein. The researchers looked for peptides that would shift to a lower energy state after binding to the HIV protein, because these would be more likely to bind to the protein and thus be capable of blocking the virus from entering a cell.

Out of millions of possible peptides, the Princeton researchers used their formula to narrow their search to five promising drug candidates, each 12 amino acids long, one-third the length of Fuzeon. Their collaborators at Johns Hopkins then tested whether the peptides were truly effective at preventing HIV from entering human cells.

The Johns Hopkins scientists found that four of the five designed peptides inhibited HIV and that one of the peptides was particularly potent, even against strains of HIV that are resistant to treatment with Fuzeon. They also found that peptides designed by the Princeton researchers were nontoxic to cells.

"One could never test all the possible peptides to see if they are effective against HIV," Floudas said. "But this model was able to sort through millions of possibilities and identify just a few that show promise."

Now that they have identified possible candidates, the researchers plan to experiment with modifying the shape of the peptides to see if they can be made even more effective against the virus. They also hope to expand the use of the model to other diseases, particularly cancers.

"It's an approach to finding peptide-based drugs that target certain proteins, whether those of a virus or those of a cancerous cell," Floudas said.

In addition to Siliciano, collaborators from Johns Hopkins included Lin Shen, a former doctoral student; Philip Cole, a professor of pharmacology; and Martin Taylor, an M.D./Ph.D. candidate who graduated from Princeton in 2005. Hoki Fung, a former Princeton doctoral student who is currently serving as a postdoctoral fellow at École polytechnique fédérale de Lausanne in Switzerland, also participated in the research.

The Hormone That Holds Key to HIV Cure. 5/2/11

Hormone "switches off" gene that orders the "surrender" of white blood cells

AllAfrica

Nairobi — Scientists have discovered a treatment that could eliminate the Aids-causing virus from the system and allow the body to cure itself. It has been known that HIV's persistent attack on the body overwhelms the defence or the immune system, eventually wearing down the white blood cells. White blood cells or T-cells are primarily responsible for fighting off foreign organisms that enter the body.

Like an army

Just like in an army that is constantly at war, the solders, in this case the white blood cells, can become exhausted and give up, leaving the body defenceless and open to opportunistic infections. In such a case, the military commander, knowing that he is fighting a losing war, may decide to surrender to avoid more damage. The body has a similar mechanism. Scientists have also discovered that overproduction and excitement of white blood cells can damage some other body tissues and sometimes lead to leukaemia, a type of blood cancer.

The overproduction of white blood cells or an overworked immune system in people with HIV and other chronic infections has been associated with the possible development of cancers and heart disease. Now Australian scientists at the Walter and Eliza Hall Institute have manipulated this mechanism to ensure the production and activation of white blood cells does not stop but goes on until HIV and other viruses have been eliminated from the body. In a press statement released by the institute on Friday, the researchers said they manipulated the gene SOCS-3, which orders the "surrender" of white blood cells, with a hormone called IL-7.

When the researchers increased levels of the hormone IL-7, the gene SOCS-3 "switched off" and the trial mice were able to gradually eliminate the HIV from their bodies, says the main study published in the February 4 issue of the journal Cell. Overwhelming infection "In an overwhelming infection like HIV, SOCS-3 becomes highly activated and suppresses the immune response, probably as a natural precaution to prevent 'out of control' responses that cause collateral damage to body tissue," Dr Marc Pellegrini, the lead researcher, said in the statement. "In the case of these overwhelming infections, the immune system effectively slams on the brakes too early, and the infection persists."

Switching off the SOCS-3 gene made sure the white cells remained active and helped the lab mice completely eliminate the infection. The switch off and immune boost were timed to be long and strong enough to eliminate the virus without causing damage to other body tissues. Dr Pellegrini said the research had provided excellent ideas for new treatments that could target and boost immune cells to fight disease, rather than targeting the disease itself. "The findings could help to develop drugs that target some of these host molecules, such as SOCS-3, and turn them off for very short, defined periods of time to reinvigorate the T-cells, allowing them to regroup to fight infection," he said.

The researchers say their work raises a real possibility for a possible cure not only for HIV but for other long-term infections, including hepatitis B and C and tuberculosis. Despite tremendous efforts, long-lived immune responses for some of these viruses are ineffective because the body is so overrun by the virus that the immune system gives up trying to battle the infection. Anti-retroviral treatment An estimated 1.5 million Kenyans are infected with HIV, of which about a third are on antiretroviral treatment. Antiretrovirals work by suppressing the replication of the virus in the body and are a life-long treatment. Like most other medicines for chronic diseases, they sometimes cause serious side effects, and a patient is advised to be in constant communication with a qualified clinician.

Early Development of Anti-HIV Neutralizing Antibodies. 14/1/11

Possibilty to design new immunogens and immunization protocols

New findings are bringing scientists closer to an effective HIV vaccine. Researchers from Seattle Biomedical Research Institute (Seattle BioMed), Vanderbilt University and the Ragon Institute of MGH, MIT and Harvard report findings showing new evidence about broadly-reactive neutralizing antibodies, which block HIV infection. Details are published January 13 in the open-access journal PLoS Pathogens.

According to author Leo Stamatatos, Ph.D., director of the Viral Vaccines Program at Seattle BioMed and a major stumbling block in the development of an effective vaccine against HIV is the inability to elicit, by immunization, broadly reactive neutralizing antibodies (NAbs). These antibodies bind to the surface of HIV and prevent it from attaching itself to a cell and infecting it. However, a fraction of people infected with HIV develop broadly neutralizing antibodies (bNAbs) capable of preventing cell-infection by diverse HIV isolates, which are the type of antibodies researchers wish to elicit by vaccination.

"We've found that the people who develop broadly-reactive neutralizing antibodies -- which are about 30% of those infected -- tend to have a healthier immune system that differs from others who don't develop those antibodies," Stamatatos explained, saying that these antibodies target only a few regions of HIV which is good from the standpoint of vaccine development. "It gives us less to target," he said.

In addition, the new findings show that these antibodies are generated much sooner than previously thought, in some cases as soon as a year after infection.

"These studies provide a strong rationale to begin teasing out the early immunological signals that allow some individuals, but not others, to mount broadly reactive neutralizing antibody responses," adds co-author Galit Alter, Ph.D.

"Now we know that these broadly-reactive neutralizing antibodies don't develop simply by chance and we can work to understand what makes this 30% of the HIV-infected population different," Stamatatos explained. By understanding that, we can hopefully use that information to design new immunogens and immunization protocols that can mimic the early events that lead to the development of such antibodies during natural infection."

High Prevalence of Asymptomatic Cardiac Abnormalities in Patients with HIV. 10/1/11

“our results support lifestyle modifications, such as smoking cessation and weight loss, as continued priorities in the chronic management of HIV infection.”

AIDSMap

Asymptomatic cardiac abnormalities are common among HIV-positive patients, US investigators report in the online edition of Clinical Infectious Diseases.  

Much higher than expected rates of structural and functional cardiac abnormalities were detected when a large number of patients were monitored using echocardiographs.

“Cardiac abnormalities were commonly detected by echocardiography, despite the relatively young age and high CD4 cell counts of the participants,” comment the investigators.

However, many of the risk factors associated with the cardiac abnormalities were potentially modifiable.

Thanks to the effectiveness of antiretroviral therapy many patients with HIV can expect to live well into older age.

But there is concern that some individuals have an increased risk of cardiovascular disease. Research suggests that patients with HIV are more likely to have a heart attack or stroke than their HIV-negative peers. The causes of this increased cardiovascular risk seem to include HIV itself, therapy with some antiretroviral drugs and traditional factors such age, smoking and diet.

Prevention of cardiovascular disease is an increasingly important component of HIV care. As many of the risks are potentially modifiable, early detection of problems means that patients can be encouraged and supported to make lifestyle changes that reduce their risk of experiencing a cardiac event.

However, little is known about the prevalence and risk factors of asymptomatic structural and functional cardiac dysfunction. Therefore investigators from the US Study to Understand the Natural History of HIV/AIDS in the ERA of Effective Therapy (SUN Study) monitored 656 patients for these abnormalities using echocardiography.

The research was conducted between 2004 and 2006. The patients had a median age of 41 years. Most (76%) were men, 71% were white, and 73% were taking anti-HIV drugs. The patients had well preserved immune function and their median CD4 cell count was 462 cells/mm³. Nearly all (91%) of the individuals who were receiving antiretroviral therapy had a viral load below 400 copies/ml.

Only a third of patients were found to have normal cardiac function and structure.

Results showed that 18% of individuals had left ventricular systolic dysfunction; 26% had diastolic dysfunction; 57% pulmonary hypertension; left ventricular hypertrophy was present in 7% of individuals, and left arterial enlargement in 40%.

The investigators note that these prevalences are much higher than those seen in the general US population. For example, in one recent study only 5% of HIV-negative patients had an enlarged left artery.

Statistical analysis showed that a range of risk factors were associated with the abnormalities observed in the HIV-positive patients.

Those for left ventricular systolic dysfunction included a history of heart attack (p = 0.019), high levels of a marker of inflammation, C-reactive protein (p = 0.033), and smoking (p = 0.036).

Diastolic dysfunction was also associated with high levels of C-reactive protein (p = 0.027) and high blood pressure (p = 0.003).

Risk factors for pulmonary hypertension included current use of the protease inhibitor ritonavir (p = 0.037).

The investigators identified high blood pressure (p = 0.002), diabetes (p = 0.003), black race (p = 0.006), elevated C-reactive protein (p = 0.15) and current treatment with abacavir (p = 0.02) as risk factors for left ventricular hypertrophy. Women with a body mass index above 25 also had an increased risk of this abnormality.

Only two factors were associated with left arterial enlargement: high blood pressure (p = 0.008) and recent use of cannabis (p = 0.013).

None of these risk factors were “unexpected” comment the investigators, and they stress that many are potentially modifiable.

They therefore conclude, “our results support lifestyle modifications, such as smoking cessation and weight loss, as continued priorities in the chronic management of HIV infection.”

Genetic Tests could Predict which Patients will have Problems with some Anti-HIV Drugs. 7/1/11

Increased chance of stopping some commonly used anti-HIV drugs in the first year because of side-effects

AIDSMap

Genetic testing could help identify patients with an increased risk of stopping some commonly used anti-HIV drugs in the first year because of side-effects, Swiss investigators report in the January 15^th edition of the Journal of Infectious Diseases.

Patients who had certain variations in certain genes were more likely to discontinue taking efavirenz (Sustiva, also in the combination pill Atripla) or ritonavir-boosted atazanavir (Reyataz).

“The study suggests that assessment of the genetic markers could lead to improved prescription of atazanavir and efavirenz,” comment the researchers.

Up to 45% of patients modify their antiretroviral therapy during the first year.  It is already known that some genetic markers are associated with an increased risk of an allergic reaction to abacavir (Ziagen, also in the combination pills Kivexa and Trizivir).

Earlier research also suggests that some genetic markers (CYP2B6, CYP2A6, and CYP3A4) may increase drug levels of efavirenz, leading to an increased risk of side-effects of the central nervous system.

For patients taking atazanavir, the genes UGT1A1, ABCB1 (MDR1) and NR112 (PXR) have been associated with hyperbilirubinemia.

Both of these side-effects have been association with treatment discontinuation.

There is also some evidence that certain genes increase the risk of elevations in lipids in patients taking protease inhibitors and of kidney problems in individuals treated with tenofovir (Viread, also in the combination pills Truvada and Atripla).

Investigators from the Swiss HIV Cohort Study wished to gain a better understanding of the relationship between 23 genetic variations and the discontinuation of therapy with atazanavir, efavirenz, lopinavir/ritonavir (Kaletra) or tenofovir within the first year.

Their study was retrospective and involved 577 patients who commenced antiretroviral therapy for the first time between 2004 and 2008.

The investigators identified 23 genetic variants from the scientific literature that have been associated with drug side-effects, and looked at the strength of the association between specific gene variants and treatment discontinuation due to adverse events, after controlling for age, body weight, sex, ethnicity, CD4 count, viral load, HIV exposure category and pregnancy.

Results showed that for neither lopinavir/ritonavir or tenofovir was there a significant relationship between genes and treatment discontinuation.

However, patients with genetic risk factors for side-effects caused by efavirenz (71% vs. 28%) and atazanavir (63% vs. 15%) were significantly more likely than individuals without these genetic profiles to discontinue therapy.

Statistical analysis showed that genetic risk factors increased the chances of efavirenz discontinuation three-fold (hazard ratio [HR] = 3.14; 95% confidence interval [CI], 1.35-7.33, p = 0.008). Genetic risk factors were associated with a nine-fold increase in the risk of discontinuing atazanavir (HR = 9.13; 95% CI, 3.38-24.69, p < 0.001).

An examination of the patients’ notes also suggested that there was a relationship between genetic risk factors and treatment discontinuation.

Drug toxicity was significantly more likely to be recorded as the reason for discontinuation for patients with genetic risk factors than those without them (efavirenz 62% vs. 12%, p < 0.001; atazanavir 33% vs. 7%, p = 0.004).

“Among 23 genetic variations included in the study, those…previously associated with plasma levels of efavirenz, and those…associated with atazanavir-induced hyperbilirubinemia were associated with early treatment discontinuation,” write the investigators.

They recommend that their study should be considered a “pilot analysis” to “provide data for power calculation, and to support further discovery efforts toward identification of additional genetic markers.”

The authors conclude “a prospective clinical trial should ideally formalize this analysis, and provide the basis for measuring the cost effectiveness of this approach.”

Population Council’s New Microbicides Protect against HIV for 24 Hours in Monkeys. 6/1/11

Study might lead to new more effective microbicidal gel

AIDSMap

Two microbicide gels each containing new agents that can prevent HIV infection protected female monkeys from vaginal infection with HIV for up to 24 hours after one application, US scientists report today in the journal PLoS One.

The research funded by the Population Council shows that a gel which combines zinc acetate and the non-nucleoside reverse transcriptase inhibitor MIV-150 protected rhesus macaques from HIV infection in every case if applied daily for two weeks, while application every other day for four weeks protected around three-quarters of the macaques from HIV infection.

Microbicides to prevent HIV infection are now a promising avenue of HIV prevention research following the results of the CAPRISA 004 trial, which showed that a microbicide gel containing the antiretroviral drug tenofovir reduced the risk of HIV infection for women by around 39%.

Antiretroviral agents from six antiretroviral drug classes are also under investigation for use in microbicides, including the non-nucleoside reverse transcriptase inhibitor dapivirine.

According to the study investigators, MIV-150 is less likely to lead to resistance than other agents of the NNRTI class, potentially making it suitable for use in a microbicide.

The investigators also tested zinc acetate, which has the potential to prevent HIV infection and also other sexually transmitted infections, such as HSV-2, the virus that causes genital herpes.

Both agents were tested individually and in combination with each other, and were delivered in a carageenan-based gel. Carrageenan is extracted from seaweed. The Population Council has previously tested a carageenan-based microbicide product, Carraguard, but found that although safe to use, it failed to protect women against HIV infection.

In this study researchers also looked at whether the products were effective when used a long time before HIV exposure. Most previous studies, in both animals and humans, have used products that were applied no more than a few hours before HIV exposure, so-called `coitally-dependent` application.

The need to apply a gel at the right time – no more than a few hours before intercourse takes place – may be one reason why almost all microbicide trials have shown that agents which look promising in the test tube or in animal studies tend not to protect against HIV infection when used by women in real-life conditions.

Good adherence – using a microbicide gel on the majority of occasion when vaginal intercourse takes place – was strongly associated with a lower risk of HIV acquisition in the CAPRISA 004 study, for example.

A `coitally independent` microbicide, which could be used each day, but at a time of the woman’s choosing rather than just before sexual intercourse, might be easier for women to use consistently.

One approach already being investigated is the use of a ring lodged at the cervix to dispense an antiviral agent in the vagina for up to a month, but approaches using a long-acting gel may also be useful, particularly if that product can protect against a range of sexually transmitted infections.

The study reported this week shows that the gel containing MIV-150 has a long-lasting effect if it is applied daily for at least two weeks, even when a very low dose of the drug is used. This may be a result of MIV-150’s tendency to accumulate in tissues, particularly in the cervical tissue.

The risk of infection appeared to be correlated with concentrations of the drug in the cervical tissue, the researchers reported. They also say that they have observed that cells exposed to MIV-150 remain resistant to HIV infection for up to five days, although these data remain unpublished.

The risk of drug resistance as a result of using antiretroviral microbicides is a concern shared by many researchers, particularly in relation to drugs in common use for antiretroviral treatment of HIV-infected people in developing countries.

No trace of MIV-150 could be found in the blood, and no drug resistance could be detected in macaques that became infected despite dosing with the microbicide containing MIV-150.

The researchers refer to unpublished data showing that resistance to MIV-150 is slow to develop in comparison to other NNRTIs, and active against viruses resistant to nevirapine, currently the most commonly used NNRTI in developing countries.

However viruses resistant to efavirenz, the other NNRTI now coming into greater use in developing countries, may have some resistance to MIV-150. This suggests that a small risk exists that the microbicide might not protect against efavirenz-resistant HIV, and further tests will be needed to investigate this question.

When used alone, MIV-150 protected 56% of macaques challenged with SHIV eight hours after the last gel application and 11% of macaques challenged 24 hours after the last gel application.

When combined with zinc acetate, the combination gel protected all 21 macaques challenged with SHIV 24 hours after the last gel application, following two weeks of daily gel application. When the gel was applied every other day for four weeks, and seven macaques were then challenged 24 hours after the last application, 67% were protected against HIV infection.

Zinc acetate was also tested for its anti-HIV effect alone, and showed a strong protective effect, protecting 11 of 14 macaques from infection. When data from daily or every-other-day dosing were pooled, the protective effect was statistically significant (70%, p<0.02).

The Population Council now plans to test both the combination product and zinc acetate as microbicides against HIV infection in phase 1 human trials which could begin in early 2012. MIV-150 was developed by the Swedish company Medivir and licensed to the Population Council in 2003.

Discovery Suggests a New Way to Prevent HIV from Infecting Human Cells. 23/12/10

Researches discovered how HIV binds to and destroys a specific human antiviral protein called APOBEC3F

Researchers at the University of Minnesota have discovered how HIV binds to and destroys a specific human antiviral protein called APOBEC3F. The results suggest that a simple chemical change can convert APOBEC3F to a more effective antiviral agent and that shielding of a common feature shared by related proteins may yield a similar outcome.

This discovery highlights the potential for a novel approach to combating HIV/AIDS that would seek to stabilize and harness the innate antiviral activity of certain human proteins, according to lead author John Albin, a researcher in the laboratory of Reuben Harris, associate professor of biochemistry, molecular biology and biophysics in the College of Biological Sciences.

Human cells produce a family of antiviral proteins (called APOBECs) that have the unique and natural ability to destroy HIV. But HIV has evolved a way to overcome restriction using an accessory protein called Vif (virion infectivity factor) to degrade the APOBEC proteins and allow the virus to spread. Albin and colleagues learned where Vif interacts with one antiviral protein, APOBEC3F, and showed how the connection can be interrupted by a simple chemical change on the surface of APOBEC3F. They also noted that similar interaction sites are found on the same surface in other members of this antiviral protein family.

"This suggests that the interaction between Vif and these antiviral APOBEC proteins could be blocked with a drug that would shield the Vif interaction region," Albin says. "Such an intervention has the potential to allow as many as seven natural antiviral drugs to spring into action and prevent HIV from spreading."

The Harris lab is focuses on understanding every level of the vital interaction between these human cellular proteins and HIV Vif. They envision that future studies will involve a more refined mapping of the physical interactions between Vif and APOBEC3 proteins, investigation of the potential for HIV to resist stabilizing changes in APOBEC3 proteins, and screens for drug-like compounds that help the cellular APOBECs destroy HIV.

John Albin, a student in the Combined MD-PhD Training Program at the University of Minnesota Medical School, and is completing a thesis under the guidance of his advisor, Reuben Harris, through the Microbiology, Immunology & Cancer Biology PhD program. His studies in the Harris lab focus on the potential of APOBEC proteins to impact HIV evolution and pathogenesis.

This latest finding builds on a body of research from Harris's lab about the relationship between HIV and APOBEC proteins. In 2003 and 2004, Harris helped discover that the APOBEC proteins have the ability to counteract HIV infection.

Harris, who won a 2009 challenge grant from the Bill & Melinda Gates Foundation to explore ways to block HIV and APOBEC3 interaction, has been studying mechanisms of mutation for nearly 20 years, first as a doctoral student at the University of Alberta, then as a post-doctoral fellow at the Laboratory of Molecular Biology in Cambridge, England, and for the past seven years as an NIH supported principal investigator at the University of Minnesota. His laboratory focuses on how mutations can be harnessed to destroy pathogens.

Nevirapine rather than Efavirenz-based HIV Treatment more Likely to Suppress Viral Load to Zero. 22/12/10

The study involved 165 patients and was retrospective.

AIDSMap

The inclusion of nevirapine rather than efavirenz in an HIV treatment combination was more likely to suppress viral load in the blood to completely undetectable levels, French investigators report in the online edition of AIDS.

A total of 81% of patients taking nevirapine (Viramune) had a viral load below 1 copy/ml compared to 55% of individuals treated with efavirenz (Sustiva). The study involved 165 patients and was retrospective. All the patients had had an undetectable viral load for at least six months and were taking either nevirapine or efavirenz in combination with FTC (emtricitabine, Emtriva) and tenofovir (Viread, the two drugs are usually combined in a single pill, Truvada, and are also available co-formulated with efavirenz in Atripla).

A viral load below 50 copies/ml is the current aim of antiretroviral therapy. Viral load tests in routine use cannot detect virus below this level. However, research assays are able to detect extremely low levels of residual viral load.

Previous research has suggested that therapy which includes a non-nucleoside reverse transcriptase inhibitor (NNRTI) is more likely to suppress viral load to extremely low levels than treatment based on a protease inhibitor. There is also some evidence that nevirapine is more effective at reducing viral load to the lowest levels than efavirenz.

French investigators wanted to gain a better understanding of the impact of nevirapine or efavirenz-containing regimens on residual viraemia. They therefore designed a retrospective study involving 75 patients treated with nevirapine and 90 individuals taking efavirenz-based therapy.

To be included in the study, patients were required to have had a viral load below 50 copies/ml for at least six months.

Viral load was monitored using an assay capable of detecting virus below 1 copy/ml.

Overall, 81% of patients taking nevirapine had a viral load of zero compared to 56% of individuals treated with efavirenz.

After controlling for potentially confounding factors, the investigators found that treatment with nevirapine was significantly more likely to suppress viral load below 1 copy/ml than therapy with efavirenz (odds ratio [OR]: 2.85; 95% CI, 1.4-6.1, p  = 0.005). The only other factor associated with a viral load of zero was the duration of viral load suppression below 50 copies/ml (OR: 2.07; 95% CI, 1.3-3.5, p  = 0.005).

The investigators believe that research now shows “the stronger ability of nevirapine than efavirenz to better control residual viremia, in patients presenting with low viremia.” They suggest that this is because nevirapine is better able to penetrate into anatomical sites that may harbour “reservoirs” of virus.

“The clinical relevance of having a viral load below 1 copy/ml has yet to be shown,” conclude the researchers, who call for studies “to explore, for example, the relationship between the level of residual viremia and systemic inflammatory or immune activation markers.”

New Discoveries Make It Harder for HIV to Hide from Drugs. 16/12/10

AIDS is chameleon-like in its replication

The virus that causes AIDS is chameleon-like in its replication. As HIV copies itself in humans, it constantly mutates into forms that can evade even the best cocktail of current therapies. Understanding exactly how HIV cells change as they reproduce is key to developing better tests and treatments for patients.I

n the Journal of Biological Chemistry and Nature Structural & Molecular Biology, MU microbiologist and biochemist Stefan Sarafianos, PhD, reveals new findings that shed light on how HIV eludes treatment by mutating. His discoveries provide clues into HIV's mechanisms for resisting two main families of drugs.

"These findings are important because identifying a new mutation that affects HIV drug resistance allows physicians to make better decisions and prescribe the proper drugs," Sarafianos said. "Without that knowledge, therapy can be suboptimal and lead to early failure."

Patients with HIV are routinely tested to track the levels of the virus and immune cells in their body. Results of the tests help physicians gauge the health of their patients and prescribe the right mix of antiviral drugs. The drugs help prevent the spread of HIV in patients by inhibiting the virus' ability to replicate.

Sarafianos' lab determined the biochemical properties that allow strains of HIV with a specific mutation -- the N348I mutation -- to escape inhibition despite treatment with Nevirapine. The drug is commonly used in combination with other antiviral medications to decrease the amount of HIV in the blood. As a result of Sarafianos' discovery, at least one major company that manufactures HIV mutation-testing kits has modified its test to detect the N348I mutation.

Sarafianos' recent findings resulted from research supported by five National Institutes of Health grants. He recently received another $417,000 award from the NIH to assist him in developing modified antibodies for HIV therapy.

"Our latest efforts to design broadly neutralizing antibodies against HIV will hopefully expand our toolbox against the virus, which remains a constantly moving target," Sarafianos said.

High Triglycerides Increase Risk of Neuropathy for Patients with HIV. 14/12/10

Association between triglyceride levels and neuropathy was independent of any other risk factor.

AIDSMap

HIV-positive patients with high triglycerides have an increased risk of neuropathy, according to US research published in the online edition of AIDS. The association between triglyceride levels and neuropathy was independent of any other risk factor.

“Since triglyceride levels were identified as a major risk for HIV-sensory neuropathy, interventions leading to reduction of triglyceride levels could reduce incidence of HIV-sensory neuropathy, a possibility that should be explored in future studies,” write the investigators.

Damage to the nerves responsible for sensation – sensory neuropathy – is common in patients with HIV. It can be an extremely painful and debilitating condition that mainly affects the feet and lower legs.

Before effective antiretroviral therapy became available, neuropathy was associated with a low CD4 cell count and a high viral load. Neuropathy has also been associated with treatment with some older anti-HIV drugs (especially d4T, ddC and ddI), as well as statins and life-style factors such as alcohol consumption.

Research involving patients with diabetes has established a relationship between high triglycerides and sensory neuropathy. A large number of patients with HIV have elevated triglycerides, due either to HIV infection or particular antiretroviral drugs. Therefore investigators from the HIV Neurobehavioral Research Center in San Diego wished to see if high triglycerides were associated with neuropathy in patients with HIV.

Their study was single centre and had a cross-sectional design. The participants were 436 HIV-positive individuals and 55 HIV-negative controls. All were seen between January 2000 and December 2009.

Most (86%) of the HIV-positive patients were men and their average age was 47 years.  Three-quarters were taking antiretroviral therapy and had an undetectable viral load. Their current median CD4 cell count was 458 cells/mm³.

Mean triglyceride levels were significantly higher in the patients with HIV than the HIV-negative controls (245 mg/dl vs. 160 mg/dl, p < 0.001)

Individuals with HIV were also significantly more likely than individuals who were HIV-negative to have signs of sensory neuropathy (27% vs. 10%).

Factors associated with neuropathy in patients with HIV included older age (p < 0.001), increased height (p < 0.001), a lower nadir CD4 cell count (p < 0.002), type 2 diabetes (p < 0.01), treatment with a protease inhibitor (p < 0.02), and use of statins (p < 0.01). Surprisingly, treatment with “d” drugs (d4T, ddC, ddI) was not associated with neuropathy.

Further analysis identified an independent relationship between high triglycerides and neuropathy.

On the basis of their triglycerides, the patients were divided three groups: low (144 patients, below 141 mg/dl), medium (145 patients, 142-243 mg/dl), and high (145 patients, above 243 mg/dl).

Patients with the highest triglycerides were almost three-times more likely than those with the lowest triglyceride measurements to have sensory neuropathy (OR, 2.6; 95% CI, 1.2-5.8).

“After adjusting for concomitant clinical and demographic factors related to HIV-sensory neuropathy, the association of HIV-sensory neuropathy with triglyceride levels persisted,” the researchers emphasise.

It is thought that neuropathy is caused by damage to mitochondria. The investigators suggest, “high triglyceride levels might lead to alteration in mitochondrial energy metabolism and membrane permeability.”

They conclude, “these findings illustrate the pathogenic complexity of HIV-sensory neuropathy to which not only HIV infection, but also its treatment, is a major contributor.”

Routine HIV care should include regular monitoring of lipid levels, and treatment of high triglycerides could not only reduce the risk of cardiovascular disease, but also help avoid neuropathy.

Bone Marrow 'Cures HIV Patient'. 13/12/10

Patient appears to have been cured of HIV

Doctors in Germany say a patient appears to have been cured of HIV by a bone marrow transplant from a donor who had a genetic resistance to the virus.

The researchers in Berlin said the man, who suffered from leukaemia and HIV, had shown no sign of either disease since the transplant two years ago.

But they stressed it was an unusual case which needed further investigation.

Experts said the result may boost interest in gene therapy for HIV.

Berlin's Charite clinic said the 42-year-old patient was an American living in Berlin, but the man has not been identified.

Genetic mutation

He had been infected with the human immunodeficiency virus, that causes Aids, for more than a decade and also had leukaemia.

The clinic said since the transplant was carried out 20 months ago, tests on the patient's bone marrow, blood and other organ tissues have all been clear.

In a statement, Professor Rodolf Tauber from the Charite clinic said: "This is an interesting case for research.

"But to promise to millions of people infected with HIV that there is hope of a cure would not be right."

Roughly one in 1,000 Europeans and Americans have an inherited genetic mutation, which prevents HIV from attaching itself to cells.

Two million people die of Aids every year and HIV is estimated to have infected 33 million people worldwide.

Option 'for a few'

Professor Andrew Sewell, from the Department of Medical Biochemistry and Immunology at the University of Cardiff said in theory a bone marrow transplant such as this one "should work" and it was surprising that no one had tried it before.

"The problem is most people with HIV live in sub-Saharan Africa and this is hugely expensive, you have to find a matched donor, and it's a pretty severe and painful operation.

"So it's going to be an option for very few people."

He added that gene therapy to knock out the mutation of the key CCR5 receptor was a possibility for future treatment.

Professor Philip Goulder, an immunologist at the University of Oxford said: "It's a really interesting case which looks at a treatment which really hasn't been thought about before.

"But without having that much information about the specific case you would want to be very cautious about getting too excited and you wouldn't be able to replicate that treatment for a lot of people with HIV."

Paul Ward, deputy chief executive at the Terrence Higgins Trust said: "This case gives us something to explore in future studies but it's certainly not a quick fix as gene therapy is complex and expensive.

"With no cure in sight, prevention should be our number one priority."

Drug-Resistant HIV Genes Identified. 12/12/10

Virus mutates at a very high rate

It is estimated that 38 million people worldwide are currently infected with HIV and that 4.1 million more are added each year. For scientists to design treatment therapies that are effective over the long-term it is essential to learn more about how the virus mutates and develops resistance to medications.

New, groundbreaking research by University of Victoria biomedical engineer Stephanie Willerth has significantly advanced the understanding of HIV and how to treat it.

"The virus mutates at a very high rate which is very problematic for HIV patients because the virus eventually develops resistance to medications,'' explains Willerth, a faculty member with UVic's Department of Mechanical Engineering and the Division of Medical Sciences.

Willerth and her team studied approximately 15,000 different versions of the virus -- something that has never been done before. This information has allowed them to locate the specific genes of the virus that were resistant to the drugs -- knowledge that could ultimately help researchers develop more effective treatments for HIV.

Willerth says that the methods she used can be applied to other difficult-to-treat viruses such as swine flu, Ebola, influenza or even staph infections.

"To study all of these different versions we have to replicate them millions of times, especially when it comes to complex viruses like HIV," explains Willerth. "Because this research method requires a large amount of genetic material and there are obvious risks of duplicating highly contagious viruses, scientists have avoided doing this. Our research was unique because of the method we used -- we isolated the genetic material from HIV, so that it was no longer alive, before we replicated it."

After replicating the virus from a small sample obtained from a long-term HIV patient who had developed drug resistance to their treatment, Willerth and her team studied its genetic make-up using "next generation" DNA sequencing -- a new method that allows researchers to study millions of molecules at a time.

Powerful New Technology to Identify HIV Inhibitors. 1/12/10

Can screen large collections of well-characterized reagents as well as raw extracts of biological specimens.

Providing long-term HIV treatment for over 33 million infected individuals worldwide requires the continuous development of new HIV therapies. Virologists at the Helmholtz Zentrum München have developed a cell-based assay system for easy, reliable identification of HIV inhibitors. This new technology can be used to screen large collections of well-characterized reagents as well as raw extracts of biological specimens.

The assay system is described in detail in the current issue of Antimicrobial Agents and Chemotherapy.

EASY-HIT is a new cell-based assay system for simple and reliable testing of HIV inhibitors. This system was developed under the leadership of Professor Ruth Brack-Werner at the Institute of Virology. At the heart of the system are cultured human cells that allow HIV to enter and replicate efficiently and that signal HIV infection by producing a red fluorescent protein. The EASY-HIT technology can be used to identify HIV-inhibitors, measure the potency of their inhibitory activity and to detect the stage of replication targeted by the inhibitor.

The researchers validated their technology with a panel of currently used anti-HIV drugs and then went on to identify 5 new HIV inhibitors. They also showed that this technology can be used to detect anti-HIV activities in raw plant extracts. The researchers are currently using this system to explore numerous biological specimens for anti-HIV activities and have already discovered novel unexpected sources of antiviral activities.

Stephan Kremb, first author of the manuscript, summarizes, "We expect the versatile and robust EASY-HIT system to identify new targets against HIV and new sources of HIV-inhibitors." "Our technology has many applications in HIV research and pharmaceutical drug design," adds Ruth Brack-Werner.

HIV was first discovered in the early 1980s and described as the causative agent of AIDS. As there is no cure for HIV infection as yet, HIV-infected individuals require life-long treatment with antiviral drugs. The problems with currently available therapies include drug side-effects, the emergence of resistant viruses and the cost of long-term treatment. "It is our particularly hope that the EASY-HIT technology will promote the development of new strategies for HIV treatment in areas with limited resources," states Ruth Brack-Werner.

Mayo Researchers Find Drug-resistant HIV Patients with Unimpaired Immune Cells. 30/11/10

It may be best to take advantage of the virus' lessened ability to kill CD4 T cells, by staying on the same medication

Rochester, Minn. -- Mayo Clinic researchers have shown why, in a minority of HIV patients, immune function improves despite a lack of response to standard anti-retroviral treatment. In these cases, researchers say, the virus has lost its ability to kill immune cells. The findings appear in the online journal PLoS Pathogens.

The goal of current treatments for HIV is to block the virus from reproducing, thereby allowing the immune system to repair itself. These findings show for the first time that not all HIV viruses are equally bad for the immune system. Patients who harbor these viruses do not develop certain complications of the disease because of mutations that render some HIV drugs ineffective -- but also impair the ability of the virus to cause disease.

"These findings suggest -- in contrast to how these patients have been treated in the past -- that changing treatments might not be needed in order to help the immune system," says Andrew Badley, M.D., Mayo infectious disease researcher and senior author of the study.

Background

HIV causes disease by progressively killing CD4 T cells, whose function is to orchestrate the immune system. Loss of these cells renders patients susceptible to unusual infections and cancers. Over time, HIV mutates and can become resistant to the drugs used for treatment. Mayo researchers have discovered that viruses with certain mutations that render a component of the drug cocktail used to treat HIV infection ineffective also have an impaired ability to kill CD4 T cells. Even though mutated viruses replicate as well as normal HIV, they fail to cause the infected cells to die. Not all mutant viruses share this effect; only selected mutations cause the impairment in cell killing, without effecting virus replication.

HIV has evolved many ways to cause the death of CD4 T cells, most of which involve HIV accelerating the normal cell death. One kind of cell death that is unique to HIV involves the HIV enzyme protease, whose normal job is to cut up viral proteins so they can be used. This same process also cuts a normal cell protein which creates a novel protein called Casp8p41. This protein is only created during HIV infection. Casp8p41 in turn is responsible for the death of many of the infected cells. Researchers found that cells infected with HIV that also contain the mutations, produced less Casp8p41, and therefore fewer of the infected cells died.

Significance of the Findings

The current treatment for HIV involves measuring virus levels in the blood and using drugs to stop that virus from reproducing. When drugs stop working, virus levels in the blood rise and physicians typically respond by changing medications. However, effective drugs may not always be available.

"Results from the current study suggest that if a patient is failing their current treatment, and other effective drugs are not available, then it may be best to take advantage of the virus' lessened ability to kill CD4 T cells, by staying on the same medication" says Dr. Badley. "We have begun to study whether the best approach might be instead to monitor Casp8p41 levels as opposed to measuring virus levels, and use that to determine whether or not to change treatment."

Researchers have already developed a way to measure Casp8p41 in the blood of patients, and this new knowledge may ultimately lead to a new diagnostic tool for HIV treatment, based upon predicting whether a patient's virus will deplete CD4 T cells.

Drug-Resistant HIV Patients With Unimpaired Immune Cells. 30/11/10

Changing treatments might not be needed in order to help the immune system

Mayo Clinic researchers have shown why, in a minority of HIV patients, immune function improves despite a lack of response to standard anti-retroviral treatment. In these cases, researchers say, the virus has lost its ability to kill immune cells. The findings appear in the online journal PLoS Pathogens.

The goal of current treatments for HIV is to block the virus from reproducing, thereby allowing the immune system to repair itself. These findings show for the first time that not all HIV viruses are equally bad for the immune system. Patients who harbor these viruses do not develop certain complications of the disease because of mutations that render some HIV drugs ineffective -- but also impair the ability of the virus to cause disease.

"These findings suggest -- in contrast to how these patients have been treated in the past -- that changing treatments might not be needed in order to help the immune system," says Andrew Badley, M.D., Mayo infectious disease researcher and senior author of the study.

Background

HIV causes disease by progressively killing CD4 T cells, whose function is to orchestrate the immune system. Loss of these cells renders patients susceptible to unusual infections and cancers. Over time, HIV mutates and can become resistant to the drugs used for treatment. Mayo researchers have discovered that viruses with certain mutations that render a component of the drug cocktail used to treat HIV infection ineffective also have an impaired ability to kill CD4 T cells. Even though mutated viruses replicate as well as normal HIV, they fail to cause the infected cells to die. Not all mutant viruses share this effect; only selected mutations cause the impairment in cell killing, without effecting virus replication.

HIV has evolved many ways to cause the death of CD4 T cells, most of which involve HIV accelerating the normal cell death. One kind of cell death that is unique to HIV involves the HIV enzyme protease, whose normal job is to cut up viral proteins so they can be used. This same process also cuts a normal cell protein which creates a novel protein called Casp8p41. This protein is only created during HIV infection. Casp8p41 in turn is responsible for the death of many of the infected cells. Researchers found that cells infected with HIV that also contain the mutations, produced less Casp8p41, and therefore fewer of the infected cells died.

Significance of the Findings

The current treatment for HIV involves measuring virus levels in the blood and using drugs to stop that virus from reproducing. When drugs stop working, virus levels in the blood rise and physicians typically respond by changing medications. However, effective drugs may not always be available.

"Results from the current study suggest that if a patient is failing their current treatment, and other effective drugs are not available, then it may be best to take advantage of the virus' lessened ability to kill CD4 T cells, by staying on the same medication" says Dr. Badley. "We have begun to study whether the best approach might be instead to monitor Casp8p41 levels as opposed to measuring virus levels, and use that to determine whether or not to change treatment."

Researchers have already developed a way to measure Casp8p41 in the blood of patients, and this new knowledge may ultimately lead to a new diagnostic tool for HIV treatment, based upon predicting whether a patient's virus will deplete CD4 T cells.

Other researchers on the team are first author Sekar Natesampillai, Ph.D.; Zilin Nie M.D.; Nathan Cummins, M.D.; and Gary Bren, of Mayo Clinic; and Dirk Jochmans, Ph.D., Tibotec BVBA, Belgium; and Jonathan Angel, M.D., Ottawa Hospital, Canada. The research was supported by the National Institutes of Health.

An Answer to a Longstanding Question: How HIV Infection Kills T Cells. 24/11/10

Virus apparently does invade those T cells, but the cells somehow block virus replication

Researchers appear to have an explanation for a longstanding question in HIV biology: how it is that the virus kills so many CD4 T cells, despite the fact that most of them appear to be "bystander" cells that are themselves not productively infected. That loss of CD4 T cells marks the progression from HIV infection to full-blown AIDS, explain the researchers who report their findings in studies of human tonsils and spleens in the Nov. 24 issue of Cell, a Cell Press publication.

"In [infected] primary human tonsils and spleens, there is a profound depletion of CD4 T cells," said Warner Greene of The Gladstone institute for Virology and Immunology in San Francisco. "In tonsils, only one to five percent of those cells are directly infected, yet 99 percent of them die."

Lymphoid tissues, including tonsils and spleen, contain the vast majority of the body's CD4 T cells and represent the major site where HIV reproduces itself. And it now appears that those dying T cells aren't bystanders exactly.

The HIV virus apparently does invade those T cells, but the cells somehow block virus replication. It is the byproducts of that aborted infection that trigger an immune response that is ultimately responsible for killing those cells.

More specifically, when the virus enters the CD4 T cells that will later die, it begins to copy its RNA into DNA, Greene and his colleague Gilad Doitsh explain. That process, called reverse transcription, is what normally allows a virus to hijack the machinery of its host cell and begin replicating itself. But in the majority of those cells, the new findings show that the process doesn't come to completion.

The cells sense partial DNA transcripts as they accumulate and, in a misguided attempt to protect the body, commit a form of suicide. Greene says that completed viral transcripts in cells that are productively infected probably don't provoke the same reaction because they are so rapidly shuttled into the nucleus and integrated into the host's own DNA.

The researchers narrowed down the precise "death window" of those so-called bystander cells by taking advantage of an array of HIV drugs that act at different points in the viral life cycle. Drugs that blocked viral entry or that prevented reverse transcription altogether stopped the CD4 T cell killing, they report. Those drugs that act later in the life cycle to prevent reverse transcription only after it has already begun did not save the cells from their death.

Those cells don't die quietly either, Greene says. The cells produce ingredients that are the hallmarks of inflammation and break open, spilling all of their contents. That may provide a missing link between HIV and the inflammation that tends to go with it.

"That inflammation will attract more cells leading to more infection," Greene said. "It's a vicious cycle."

The findings also show that the CD4 T cells' demise is a response designed to be protective of the host. All that goes awry in the case of HIV and "the CD4 T cells just get blown away," compromising the immune system.

Greene said that all the available varieties of anti-HIV drugs will still work to fight the infection by preventing the virus from spreading and reducing the viral load.

The findings may lead to some new treatment strategies, however. For instance, it may be possible to develop drugs that would act on the cell sensor that triggers the immune response, helping to prevent the loss of CD 4 T cells. His team plans to explore the identity of that sensor in further studies. They also are interested to find out if the virus has strategies in place to try and prevent the CD4 T cells' death.

"The cell death pathway is really not in the virus's best interest," Greene says. "It precludes the virus from replicating and the virus may have ways to repel it."

HIV Drugs Interfere With Blood Sugar, Lead to Insulin Resistance. 22/11/10

Powerful drugs that have extended the lives of countless people with HIV come with a price

The same powerful drugs that have extended the lives of countless people with HIV come with a price -- insulin resistance that can lead to diabetes and cardiovascular disease.

Now, researchers at Washington University School of Medicine in St. Louis have determined why that happens. Their research shows that HIV protease inhibitors directly interfere with the way blood sugar levels are controlled in the body. This leads to insulin resistance, a condition that occurs when the body produces enough insulin but doesn't use it properly.

This confirmation provides the potential to develop safer antiviral drugs.

Paul Hruz, MD, PhD, assistant professor of pediatrics and of cell biology and physiology at the School of Medicine, and his team found that first-generation protease inhibitors, including the drug ritonavir, block GLUT4, a protein that transports glucose from the blood into the cells where it is needed. This raises blood sugar levels -- a hallmark of diabetes.

"Our lab has established that one of the effects of these drugs is blocking glucose transport, one of most important steps in how insulin works," says Hruz, senior author of the study published in the Nov. 19 Journal of Biological Chemistry. "Now that we've identified the main mechanism, we will look to develop new drugs that treat HIV but don't cause diabetes."

Hruz's lab made the discovery in mice that lacked the GLUT4 protein. When researchers gave these mice ritonavir, the drug had no effect on their glucose tolerance. However, when they gave the drug to normal mice, their blood glucose shot up very quickly, showing that the drugs impair glucose tolerance and promote insulin resistance.

"What we saw were very acute effects on insulin sensitivity that we could reverse in the mice," Hruz says. "But when insulin resistance goes on for a long time, secondary changes develop, such as high triglycerides, and those are harder to reverse," he says.

The finding will help researchers better understand the role of glucose transporters in health and disease, including the epidemic of type 2 diabetes in HIV negative patients, says Hruz. He expects the results will help scientists better understand how to develop new diabetes drugs and the role of glucose transport in diseases such as heart failure.

Hruz and his team are now studying at the molecular level how the HIV drugs inhibit GLUT4.

"We'd like to figure out exactly how these drugs interact with the transporter to aid the development of better HIV drugs," he says. "We want to find problems in glucose transport that lead to diabetes in the preclinical stage of drug development."

The team already is working with a drug developer to create a new HIV drug that the virus does not develop resistance to and does not block GLUT4.

Vyas A, Koster J, Tzekov A, Hruz, P. Effects of the HIV Protease Inhibitor Ritonavir on GLUT4 Knock-out Mice. Journal of Biological Chemistry. Nov. 19, 2010.

Discovery in How HIV Thwarts the Body's Natural Defense Opens Up New Target for Drug Therapies. 21/11/10

Natural killer cells are powerless against HIV, a fact that has bedeviled science for over 20 years.

Natural killer cells are major weapons in the body's immune system. They keep the body healthy by knocking off tumors and cells infected with viruses, bombarding them with tiny lethal pellets. But natural killer cells are powerless against HIV, a fact that has bedeviled science for over 20 years.

Now, researchers at Rush University Medical Center have discovered the reason why.

The study, posted online this week in the peer-reviewed journal Cell Host & Microbe, marks the "beginning of a fascinating story that will shed new light on an important but still poorly understood aspect of the interaction of HIV with natural killer cells," according to an editorial in the journal.

"With this information, we now have a major new target for drug therapies that could potentially stop HIV and allow the body's natural killer cells to do what they are designed to do -- protect the body from this lethal virus," said Edward Barker, PhD, associate professor of immunology and microbiology at Rush University and lead author of the study.

HIV, like any virus, is bent on producing progeny. It infects a cell, replicates itself over and over, and spreads throughout the body by using its "accessory" proteins to both take over the machinery of the cells it inhabits and thwart the arsenal of immunological cells that might destroy it.

Oddly, some of these proteins work at cross purposes. One, the Vpr protein, initiates what is called DNA damage repair, stopping the host cell in its tracks so that the virus can take over. But that action also sends a message to the cell surface that something is amiss. A ligand, called ULBP, is sent to the surface of the cell, which the prowling natural killer cells recognize and latch onto -- the initial steps just before moving in for a kill.

Meanwhile, another protein produced by HIV prevents the cytotoxic T cells of the immune system from homing in on the HIV-infected cell and obliterating it. But this same protein also provokes the natural killer cells into action by shutting down an inhibitory mechanism that would hold the killer cells back.

If all worked as it should to protect the body from HIV, the natural killer cells would start firing their lethal pellets. But they don't, and that is what has puzzled scientists for so long.

"The barrel of the shotgun is loaded, but the trigger still has to be pulled," said Barker.

Barker and his colleagues now know why the trigger is not pulled: because yet another protein, called NTB-A (for Natural killer T-cell and B-cell Antigen), has virtually disappeared from the surface of the infected cell. Without NTB-A in place, the natural killer cells don't start firing the guns.

The culprit, the researchers found, is a protein made by HIV called Vpu, which holds NTB-A inside the cell and prevents it from reaching the cell surface.

When the researchers altered the Vpu protein, allowing NTB-A to migrate to the cell membrane, the natural killer cells blasted the HIV-infected cells -- proof that both the ULBP ligand and NTB-A are needed before the natural killer cells will start shooting.

Barker said that the finding is extremely exciting not only because it resolves a longstanding puzzle in how HIV is able to evade the body's innate immune response but also because it opens up new possibilities for combating HIV.

Other researchers at Rush involved in the study were Anker Shah, PhD, Bharatwaj Sowrirajan, BS, Zachary Davis, BS, and Jeffrey Ward, MD, PhD. Scientists at Loyola University and the University of Utah were also involved. The researresearch was funded by a grant from the National Institutes of Health.

Designing More Effective Anti-HIV Antibodies. 20/11/10

Most of these antibodies are strangely ineffective at fighting the disease

Although people infected with HIV produce many antibodies against the protein encapsulating the virus, most of these antibodies are strangely ineffective at fighting the disease. A new study suggests why some of the most common of these antibodies don't work: they target the protein in a form it takes after the virus has already invaded the cell, when it's too late, report researchers at Children's Hospital Boston and their colleagues.

The findings, published online Nov. 14 in the journal Nature Structural & Molecular Biology, refocus attention on the rare group of neutralizing antibodies that do work, described by the team in an earlier study. These antibodies home in on the protein at an earlier moment when the virus latches onto a healthy cell. Many people believe an effective HIV vaccine will need to greatly expand this rare antibody immune response to block infection. Children's has filed for patents on two new proteins designed to expand this rare antibody response.

"The key finding of this paper is that we can distinguish the shape of the protein targeted by useful antibodies," said senior author Bing Chen, PhD, of the Division of Molecular Medicine at Children's. "That means we can think about designing immunogens trapped in this defined structure and ways to prevent the protein from forming into an irrelevant conformation."

The same HIV protein, known as gp41, takes two such dramatically different configurations that it reacts with two different kinds of antibodies, Chen's group shows. In HIV, the protein travels under wraps on the surface of virus particles. When the virus locks onto a healthy cell, the protein briefly unfolds and stretches out to its full length, extending out like a person reaching high overhead. This is the shape that generates rare but useful neutralizing antibodies in some people.

Then comes another shape change. After taking hold of the cell membrane, the protein folds over, like a person touching his toes, to fuse the cell to the virus membrane. That final calisthenic to fuse the membranes also creates an opening that allows the viral contents to invade the cell. At this stage, the protein functions as a decoy, serving only to bring on fruitless antibody responses and to distract the immune system, the authors wrote in the paper.

"We now believe that the neutralizing antibodies bind to the intermediate state, which prevents further structural rearrangements and blocks membrane fusion," said Chen, who is also affiliated with Harvard Medical School. "The key is that we can now separate which antibody recognizes which state, so that we can move forward to design an immunogen to induce an effective antibody response."

The findings suggest a new way of generating more useful anti-HIV antibodies. The intermediate stage of the protein normally lasts only about 15 minutes, too quickly to mount a successful immune response. For earlier work, the team leveraged the power of the first fusion-inhibiting antiviral drug, T20 (enfuviritide), approved for late-stage disease when other treatment options are failing. The drug traps the protein in the shape that spurs useful antibodies, the researchers reported in an earlier paper. In the latest study, the team further refined the protein for this study in a variation that does not require the drug. Additional biochemical experiments confirmed that two rare neutralizing antibodies from patients tackled the fleeting intermediate state of the experimental protein.

"This paper helps to resolve key questions plaguing the field: Why do certain forms of the protein interact with certain antibodies, and why aren't these antibodies in general more effective?" said virologist Dan Barouch, professor of medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, who was not involved in the study. "This paper shows how particular antibodies react with different conformation states of gp41, but the implications are well beyond that. The results also offer a new way of thinking about envelope immunogen design." Barouch is collaborating with Chen to test the immunogenicity of the protein in animal models.

Chen's team discovered the immune-evasion power of the decoy protein shape in studies led by Gary Frey, PhD, and Jia Chen, PhD. Frey and Chen solved the atomic structure of a useless antibody bond to the final form of the protein. "The postfusion state is very stable," said Chen, allowing plenty of time for the body to churn out worthless antibodies.

A companion paper from a Duke University group published simultaneously online shows another non-neutralizing antibody binding to a slightly different region of the protein in the postfusion form, further confirming the findings reported by Chen's group.

Funding: US National Institutes of Health; a Collaboration for AIDS Vaccine Discovery grant from the Bill and Melinda Gates Foundation; the Center for HIV/AIDS Vaccine Immunology; the Department of Veterans Affairs; and the Ragon Institute of MGH, MIT and Harvard.

Cellular Protein Hobbles HIV-1. 16/11/10

BST-2 known to interfere with the spread of human immunodeficiency virus type 1

A cellular protein called BST-2 had already been known to interfere with the spread of human immunodeficiency virus type 1 (HIV-1), by inhibiting the release of its progeny particles from infected cells. Now a team from McGill University, Montreal, shows that in addition, each progeny virion's ability to cause infection is severely impaired.

"BST-2 may exert a more potent inhibition effect on HIV-1 transmission than previously thought," says coauthor Chen Liang. The research is published in the December Journal of Virology.

BST-2 appears to attenuate infectivity of progeny particles by interfering with their maturation. Normally, during synthesis of new virus particles, a protein called PR55Gag is cleaved into three major structural proteins of HIV. "This cleavage process transforms HIV-1 from an immature and non-infectious virion into a mature and infectious virion," says Chen. The protease inhibitors, drugs given to AIDS patients to contain the disease, block this step. Similarly, BST-2 seems to interfere with this step, because in the study, its presence was associated with accumulation of uncleaved Gag precursor and intermediate products. The mechanism of that interference has yet to be elucidated.

BST-2 (bone marrow stromal cell antigen-2), also known as tetherin, is a cellular protein which has been shown to restrict production of enveloped viruses besides HIV-1, including HIV-2, simian immunodeficiency virus, Kaposi's sarcoma herpes virus, Lassa virus, Marburg virus, and Ebola virus. It interferes with release of new virus particles by anchoring one end of itself in the plasma membrane of the infected cell while the other end becomes inserted into the viral envelope.

Different viruses have evolved various countermeasures. For example, in the case of HIV-1, the viral protein Vpu downregulates BST-2 from the cell surface, removing it from virus budding sites.

"The antiviral function of BST-2 has been extensively studied by a number of groups besides ours," says Chen. "Our hope is that the results of all of these studies can eventually be used to develop a BST-2 based anti-HIV-1 therapy."

Discordant HIV Levels in the Brain and Blood Are More Common Than Expected. 15/11/10

Up to 10 percent of people on antiretroviral (ARV) therapy have active HIV replication in the brain and spinal fluid

Up to 10 percent of people on antiretroviral (ARV) therapy have active HIV replication in the brain and spinal fluid despite having undetectable HIV levels in the blood, according to a study published online November 4 in The Journal of Infectious Diseases. This could explain why low-level inflammation and cognitive decline persist in people being successfully treated with HIV drugs. It may also have implications for treatment recommendations and the ongoing study of different treatment strategies.

A number of studies in recent years have documented two key findings about HIV in the brains of people taking ARVs. First, that HIV reproduction in the brain and central spinal fluid (CSF) is sometimes different from what occurs in the blood; and second, that immune inflammation and cognitive decline are frequently detected in people who otherwise have very good control of their HIV on ARV therapy.

Another key factor that some researchers believe can significantly affect HIV’s activity in the brain and CSF is the ability of individual drugs to cross the blood-brain barrier. Some ARVs cross easily, while others have poor penetration into these compartments.

In an effort to explore the interaction of these three factors—differences in viral replication in blood and brain, signs of immune inflammation, and the brain penetration potential of a person’s regimen—Arvid Edén, MD, from the Sahlgrenska Academy at the University of Gothenburg, in Sweden, and his colleagues examined blood and CSF samples from 69 HIV-positive people taking ARV therapy.

The blood and brain samples were taken between 2002 and 2010. To be included in the study, in which CSF levels were obtained by a lumbar puncture, a person needed to have been on ARVs for at least six months and to have had undetectable HIV levels in the blood for at least three months. All of the people were taking either Sustiva (efavirenz), Norvir (ritonavir)-boosted Reyataz (atazanavir) or Kaletra (ritonavir plus lopinavir). These drugs were combined with either Viread (tenofovir), Ziagen (abacavir) or Retrovir (zidovudine), plus either Emtriva (emtricitabine) or Epivir (lamivudine).

Edén and his colleagues found that 10 percent of the participants had detectable HIV levels in CSF, many more than they expected.

When the team compared the characteristics of those with measurable virus in CSF with those who did not have measurable virus in CSF, they found that people with measurable CSF levels were more likely to have been on ARVs longer, to have had periodic increases in HIV in the blood (blips), and to have taken a treatment interruption.

Edén’s team also found that people with measurable CSF HIV levels were more likely to have high levels of brain inflammation, as determined by measuring neopterin levels.

The makeup of the ARV regimen was not statistically meaningful in regards to discordant viral load responses in the blood and brain. However, there was a trend toward an increased risk of HIV replication in the brains of those who took either Viread or Ziagen compared with those who took Retrovir.

Interestingly, a new method of calculating the likelihood of good ARV control of HIV in the brain, called the central nervous system penetration effectiveness (CPE) rank, was not a good predictor of neither discordant blood and brain HIV levels nor the likelihood of brain inflammation.

Though the brain penetration of the regimens did not significantly affect the likelihood of having discordant HIV levels in the blood and brain, other studies have found that it does. In an accompanying editorial, David Clifford, MD, from Washington University in St. Louis, said this issue needs critical attention, as the most commonly used ARVs today often have only minimal to moderate brain penetration. “If these findings are replicated by others, suggesting 10 percent failure rate of current therapy in the critical CNS compartment, this would be a serious shortcoming for present therapy,” he warned.

“This topic also touches on the interaction of HIV with aging, particularly as it affects the brain and cognitive status,” he continued, noting that cognitive decline from HIV replication and activation could hasten or worsen age-related cognitive problems.

“If control of virus in the brain becomes increasingly difficult to maintain over time,” he concluded, “this implies that increasing neurologic symptoms associated with the virus might augment the cognitive decline of aging, resulting in much more serious late-life neurological issues for HIV-infected patients."

Ultimately, both doctors, along with Edén’s colleagues, emphasize that this is a very important area of exploration that demands larger studies going forward.

X-rays Illuminate the Mechanism used by HIV to Attack Human DNA. 11/11/10

Imperial scientists have made an important advance in understanding how retroviruses infect human cells.

Scientists from Imperial College London have used data collected at Diamond Light Source, the UK’s national synchrotron facility, to advance the understanding of how HIV and other retroviruses infect human or animal cells. The research, which is funded by the Medical Research Council, is published in Nature today.

Using Diamond’s finely tuned pinpoint X-ray beams, the researchers were able to determine 3D structures of the key molecular machine used by viruses, such as HIV, to insert copies of their genetic material into host DNA.

This fundamental knowledge will not only facilitate design of better drugs for fighting AIDS, but may also have an impact on pioneering treatments such as gene therapy, an experimental technique using tamed versions of viruses to treat genetic disorders. One condition this could help is "bubble boy" disease, a condition where a defective gene leaves sufferers with little or no immune system, making them extremely vulnerable to infectious diseases and in some cases having to live permanently inside a sterile environment.

HIV and other retroviruses carry their genetic material as RNA. After entering a human or animal cell, they convert their genomic RNA into DNA, which is then inserted into one of the cell's chromosomes. To accomplish this, retroviruses use integrase, an enzyme that brings the ends of the viral DNA and cellular DNA together. It then irreversibly joins the DNAs, making the infected cell carry the viral genome permanently.

Earlier this year, the researchers announced an initial breakthrough, when they determined the structure of integrase from the prototype foamy virus (PFV) assembled on viral DNA ends. Crucially, because PFV is very similar to HIV in the way it integrates its DNA, the structures allowed them to explain how an important class of HIV drugs disable integrase.

Now the group has determined 3D structures of PFV integrase bound to both viral and cellular DNA. These new structures elucidate how integrase attacks cellular DNA and the mechanics of irreversible insertion of viral DNA. "It has truly been a breathtaking ride," said lead researcher Dr Peter Cherepanov, from the Department of Medicine at Imperial College London. "Only 18 months ago we had a rather sketchy understanding of retroviral integration. Now we have obtained snapshots depicting the whole process in atomic detail. The new 3D structures capture the retroviral integration machine in action."

These findings may enable improvements in gene therapy to correct gene malfunctions. A disabled version of a retrovirus can be used to insert a functional copy of a gene into a human chromosome. Although such approaches have proven quite successful, they are still experimental, requiring more work to make them safer.

Dr Cherepanov explains how his group’s latest findings could help. "One of the main problems with the current method is that retroviral integration is too random. While being very efficient, by its nature, integration is not very selective with respect to its target, the chromosomal DNA. Ideally, we want to insert therapeutic genes in pre-defined, safe locations of the human genome.

"Using the new structural information we have uncovered, researchers can now start trying to tweak the retroviral integration machinery to make it more suitable for practical applications. For example, we might be able to design integrase that would be highly selective for target DNA sequence."

The structural data collection was carried out on the I02 macromolecular crystallography experimental station at the Diamond synchrotron in Oxfordshire. Principal Beamline Scientist, Professor Thomas Sorensen, said: “This kind of fundamental research is vital if we are to advance our understanding of the viruses and diseases that affect millions of people around the world. Knowing the 3D structure of the mechanisms involved is like being able to see inside the engine of your car. If you can actually see what is happening, you get an idea of how you can fix it. At Diamond we produce the extremely intense X-ray beams required for looking at the molecular interactions involved in a variety of biological processes."

Advances in structural biology have accelerated greatly as a result of access to the synchrotron facilities that have been developed around the world in the past 25 years. Biologists have been swift to recognise the huge potential that lies behind understanding the multitude of processes that take place within living organisms at a molecular level. Researchers in the UK are at the forefront of this work and Diamond Light Source plays its part in providing cutting edge facilities for protein structure determination. Diamond currently has five experimental stations dedicated to structural biology as well as an on-site membrane protein laboratory. Previous breakthroughs using structural data from Diamond include gaining a better understanding of hypertension in the pre-natal condition pre-eclampsia, learning how a key tuberculosis drug is activated, understanding how bird flu can affect humans, and solving the 3D atomic models of a single transporter protein responsible for the movement of essential chemicals into cells of the body.

Journal reference:

N. Goedele et al. The mechanism of retroviral integration through X-ray structures of its key intermediates. Nature, 11th November 2010

Scientists Unveil Mechanisms of Immune Reconstitution Inflammatory Syndrome. 10/11/10

Newly research sheds light on a poorly understood Immune Reconstitution Inflammatory Syndrome

Newly published research by scientists at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, sheds light on a poorly understood, acute illness called Immune Reconstitution Inflammatory Syndrome (IRIS) that develops in some HIV-infected individuals soon after they begin antiretroviral therapy.

IRIS affects certain HIV-infected individuals whose immune systems are heavily damaged by the virus and who have a treated or undiagnosed AIDS-associated infection. When these individuals start antiretroviral therapy and their immune cells begin to regenerate, the immune system unexpectedly produces an exaggerated response that unmasks or worsens the symptoms of the co-infection. IRIS has become a notable challenge in treating HIV disease, particularly in resource-limited settings. The scientists hope that better understanding how and why the syndrome occurs will lead to targeted prevention or therapy.

To find immunologic patterns that distinguish individuals who develop IRIS from those who do not, the researchers analyzed blood samples from HIV-infected individuals, focusing their analysis on a group of immune cells called T lymphocytes. Most of the studied patients had an AIDS-associated fungal, viral or bacterial infection before they started antiretroviral therapy.

The analysis showed that the individuals who developed IRIS had a higher proportion of activated T cells before starting antiretroviral therapy compared with those who did not develop IRIS. These activated T cells had the propensity to make a key infection-fighting molecule called interferon gamma both before therapy began and during IRIS episodes, suggesting that the cells may participate in the exaggerated immune response seen during IRIS. In addition, the surface markers expressed by the T cells -- some with a stimulatory effect and some restraining in nature -- suggested they were highly activated as a result of an encounter with the microbes co-infecting the HIV-infected individuals.

A companion study describes a new animal model that can be used to directly analyze the immunologic mechanisms that cause IRIS. This model employs mice infected with Mycobacterium avium, a pathogen frequently seen in HIV-infected individuals who develop IRIS. To mimic the immunologic condition of IRIS-susceptible HIV-infected individuals, the researchers began with mycobacterium-infected mice that had extremely low numbers of T cells. The scientists found that rebuilding the population of T cells in these mice, as usually occurs during antiretroviral therapy in humans, triggered an IRIS-like disease. In addition, the researchers observed that interferon-gamma production by the repopulating T cells in the mice clearly facilitated the development of experimentally induced IRIS. The study also implicated a type of immune cell known as a macrophage in sparking IRIS in the mice.

Bone Loss Common in Patients with HIV, and Often Progresses. 8/11/10

High prevalence of low bone mineral density among patients with HIV

AIDSMap

There is a high prevalence of low bone mineral density among patients with HIV, Spanish investigators report in the online edition of AIDS. The researchers also found evidence during follow-up of deterioration of bone health in many patients.

“Our…study revealed a marked incidence of low BMD [bone mineral density] in a large number of patients with long-term HIV infection and prolonged antiretroviral therapy”, comment the researchers.

They believe that their findings have immediate clinical significance, and write: “Clinical monitoring of BMD by DXA scan should be a priority in HIV-infected patients, specifically in those at risk of fracture.”

HIV infection has been firmly linked with an increased risk of low bone density. However, the exact causes are unclear.

Traditional risk factors for this condition include smoking, heavy alcohol consumption, malnutrition, low body weight, and lack of physical activity.

HIV itself can cause loss of bone mineral, and treatment with some anti-HIV drugs has also been associated with loss of bone mineral density.

Spanish researchers wanted to gain a better understanding of the prevalence, risks, and progression of bone loss in their HIV-positive patients.

They therefore designed a retrospective study involving 671 patients who received HIV care between 2000 and 2009 in Barcelona. All the patients had at least one DXA scan. Progression of bone loss was assessed in 391 individuals who had two or more scans.

Most (72%) of the patients were male, 6% were aged over 55, the median age was 42 years (interquartile range 37 - 47), 67% had a body mass index (BMI) within the normal range, 62% had an adequate calcium intake, and 35% were co-infected with hepatitis B or C.

CD4 cell count at the time of entry to the study was 496 cells/mm³, 93% had experience of antiretroviral therapy, and 61% had an undetectable viral load.

The patients had been taking anti-HIV drugs for a median of seven years, 53% were taking a protease inhibitor, and the same proportion of patients took tenofovir (Viread, also in the combination pills Truvada and Atripla).

Osteopenia – mild bone loss – was diagnosed in 47% of patients and osteoporosis – porous bone with an increased risk of fractures -  in 23%.

Factors associated with low bone mineral density were increasing age (p < 0.001), low BMI (p < 0.001), male sex (p = 0.0078), high creatinine levels (p = 0.0047), taking HIV therapy at the time of DXA scan (p = 0.007), longer duration of antiretroviral treatment (p = 0.004), and increased amount of time taking a protease inhibitor.

Next the investigators looked at the progression of bone loss. Their analysis included the patients who had two or more DXA scans.

The median time between the first and last scan was 2.5 years, but in 27% of patients it was more than five years.

At the first scan, 49% of patients had osteopenia and 22% osteoporosis. At the second scan this had increased to 50% and 27%.

Overall, 29% of patients experienced progression to low bone mineral density, including 13% progressed to osteopenia, and 16% from osteopenia to osteoporosis.

When analysis was restricted to the 105 patients with five or more years of follow-up, 47% lost bone mineral density, including 18% who developed osteopenia and 29% who developed osteoporosis.

Factors associated with bone loss during follow-up included increasing age (p < 0.0001), male sex (p < 0.0001), low BMI (p < 0.0001), longer duration of treatment with a protease inhibitor (p < 0.0001) or tenofovir (p < 0.0001), and taking a protease inhibitor at the time the DXA scan was performed (p < 0.0001).

“We reveal a high prevalence of low BMD in our cohort. The longitudinal analysis – more than five years of follow-up in some cases – revealed rapid progression to deminiralization”, comment the investigators.

The investigators stress the need “for close monitoring of BMD, specifically in at-risk patients who are taking antiretroviral therapy that affect bone demineralization.”

Researchers Unravel a Secret of HIV Controllers. 5/11/10

Five amino acids prevents HIV progression to AIDS

Five amino acids—tiny fragments of a protein called HLA-B—are what separate an elite group of HIV-positive people who naturally do not progress to AIDS from those living with the virus who will invariably develop AIDS without lifelong antiretroviral treatment, according to an important paper published November 4 on the website of the journal Science.

Under the direction of Bruce Walker, MD, from the Ragon Institute of Massachusetts General Hospital in Boston, a team of researchers sorted through 1.4 million bits of DNA to determine the rare gift of HIV control and immune system health among untreated long-term nonprogressors (LTNPs). The hope is that once researchers identify this gift, they can then replicate it in HIV-positive people with progressive disease. 

“HIV is slowly revealing its secrets, and this is yet another,” Walker said. “Knowing how an effective immune response against HIV is generated is an important step toward replicating that response with a vaccine. We have a long way to go before translating this into a treatment for infected patients and a vaccine to prevent infection, but we are an important step closer.”  

It has been known for almost two decades that a small minority—about one in 100—of individuals infected with HIV are able to live with HIV infection without showing any symptoms of disease progression, despite having a detectable viral load. Even more unique is a subset of LTNPs known as HIV controllers, who maintained undetectable viral loads, in the absence of treatment, without any obvious signs of immune system damage.  

In an effort to better understand this rare ability, researchers have been exploring genetic differences between LTNPs and HIV progressors. This led to the creation of the International HIV Controllers Study in 2006 by Florencia Pereyra, MD, of the Ragon Institute and her colleagues. The initial goal was to enroll 1,000 HIV controllers from medical clinics and research institutes around the world. That goal was expanded to 2,000 controllers in 2008, and thus far more than 1,500 controllers have been enrolled.

Early research suggested that certain genes involved with the HLA system—molecules that help the immune system differentiate between “self” and “invaders”—were important for HIV control. “But they couldn’t tell us exactly which genes were involved and how they produced this difference,” explained Paul de Bakker, PhD, of the Brigham and Women’s Hospital in Boston and a coauthor of the study. “Our findings take us not only to a specific protein, but to a part of that protein that is essential to its function.”

The current investigation began with a genome-wide association study (GWAS) of almost 1,000 controllers and 2,600 individuals with progressive HIV infection. The GWAS, which tests variations at a million points in the human genome, identified some 300 sites that were statistically associated with immune control of HIV, all in regions of chromosome 6 that code for HLA proteins. Further analysis narrowed the number of gene sites to four but could not indicate whether those differences actually affected viral control or were just located near the causal variants. Fully sequencing that genome region in all participants was not feasible, but a process developed by Sherman Jia—a medical student in the Harvard-MIT Health Sciences and Technology program—pinpointed specific amino acids; and directly testing those sites associated five amino acids in the HLA-B protein with differences in viral control. 

HLA-B is essential to the process by which the immune system recognizes and destroys virus-infected cells. Usually HLA-B grabs onto viral protein segments called peptides that are inside the cell and carries them to the cell membrane where they essentially flag the infected cell for destruction by CD8 “killer” T cells. The portion of the HLA-B protein that grabs and displays viral peptides is called the binding pocket, and all of the five identified amino acid sites are in the lining of the binding pocket.

“Amino acid variation within the HLA-B binding pocket will impact its shape and structure, probably resulting in some peptides being presented effectively and others not,” de Bakker says.  “Our work demonstrates that these variants could make a crucial difference in the individual’s ability to control HIV by changing how HLA-B presents peptides from this virus to the immune system.” 

This research’s ultimate goal is to clarify the mechanisms in which nonprogressors naturally control HIV and then to use that information to design a vaccine. “If we can replicate the natural phenomenon seen in HIV controllers (low levels of virus loads without medication) then we can impact the epidemic by decreasing HIV transmission and disease progression,” said Paul McLaren, a postdoctoral fellow at the Broad Institute in Cambridge and another coauthor of the study. “There are a lot of steps between now and then, but that’s the ultimate goal.”

Gene Research Finds Clues to AIDS Survival. 5/11/10

Why were they able to survive with the AIDS virus, free of symptoms and the need for potent drugs?

Boston

For decades, they lived a mystery: Why were they able to survive with the AIDS virus, free of symptoms and the need for potent drugs, while so many others with the same germ turned deathly ill?

Their innate ability to keep HIV infections in check intrigued researchers, who suspected these people, known as “controllers,’’ might carry clues to designing effective vaccines after nearly 30 years of frustration.

Now, an international team of researchers, led by specialists in Boston, has cracked these HIV survivors’ genetic code, sifting through almost 1.4 million pieces of DNA to discover five amino acids that separate the small cadre of controllers from the vast majority who must take medication or face death.

Although authors of the study released yesterday cautioned that a vaccine remains years away, the discovery is testament to genetic tools that did not exist even a few years ago and to intellectual cross-pollination among hospitals, universities, and research institutes in Boston and Cambridge.

It also reflects the tenacity of scientists who were once dismissed with skepticism and of patients who were part of the AIDS epidemic but were not touched in the same way as friends and relatives dying all around them.

The discovery was reported on the website of the journal Science. The researchers said the differences they found cause small changes on the surface of HIV-infected cells, which could alter the immune system’s response to the virus.

“HIV is slowly revealing its secrets,’’ said Dr. Bruce Walker, one of the leaders of the international consortium and director of the Ragon Institute, an AIDS-vaccine research center affiliated with Massachusetts General Hospital, Harvard University, and MIT.

“We’ve now been able to go from a haystack down to a needle and see that this is really the key place where we need to focus our effort,’’ he said.

Doctors not involved with the research said they hoped the findings would hasten development of an AIDS vaccine at a time when the world struggles to provide drugs to the 33 million people already infected.

Dr. Calvin Cohen, research director for Community Research Initiative of New England, which conducts AIDS-treatment trials, said that while the discovery “doesn’t mean we should start opening the champagne tomorrow, it does seem to me there are reasons to pursue this observation and see if we can mimic this in some therapeutic manner.’’

This medical detective story traces its roots to San Francisco. In the early days of the epidemic in the 1980s, it seemed virtually everyone infected with HIV was dying within months or a few years of diagnosis.

Then, researchers who had collected blood from gay men years earlier for a hepatitis B study reanalyzed the stored blood and recognized that some of the men had already been infected with HIV. But medical exams done years later found that those men had none of the classic signs of the disease: no fever, no pneumonia, no opportunistic infections.

Doctors were seeing the same thing in their clinics. “When I was interacting with individuals on a one-to-one basis, they didn’t know what was going on; they didn’t know how long it would last,’’ said Dr. Steven Deeks, an HIV specialist at the University of California, San Francisco. “There was this survivor guilt — they were surviving and their friends had not.’’

Walker was enlisted in the early 1990s to perform analyses of controllers’ blood and found that their ability to control the virus almost certainly had nothing to do with the virus itself — they weren’t infected with a feeble form of HIV, for example. Instead, researchers began to suspect the answer must be sewn into genes, especially those involved with letting the virus enter cells or those governing the body’s immune response.

But it would take the genetics revolution — and a dinner at the home of Lawrence H. Summers, then Harvard’s president — to translate a finding in the clinic to a major discovery in the laboratory. At that soiree, Walker encountered Eric Lander, a genetics pioneer and founding director of the Broad Institute, a leading genomics research center in Cambridge. They discussed harnessing the growing might of genetics to explore the mysteries of AIDS.

Walker carried his idea back to Mass. General and shared it with Dr. Florencia Pereyra, then training to become an infectious disease specialist. She was enthusiastic about the project but saw soon enough that not everyone shared that zeal.

“There were a lot of skeptics along the way,’’ Pereyra said. Initially, the Boston researchers could not gin up grants from the usual sources, such as the National Institutes of Health. Instead, an investment banker named Mark Schwartz provided early support four years ago, and the NIH provided money later.

It’s estimated that only one of every 300 people infected with HIV is a controller, but such patients provided copious blood samples by the hundreds for Pereyra’s and Walker’s study.

“They could say, ‘What the hell, why do I care? I’m controlling the virus,’ ’’ Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said of controllers in the study. “But instead, they’re willing to participate in this kind of research.’’

The study involved genetic analyses of 974 controllers and 2,648 patients whose HIV infections had progressed.

Earlier research had identified the genetic neighborhoods in which most of the variation among humans dwells. So it was those areas of DNA where researchers hunted for differences among the HIV-infected.

When viruses invade the body, they hijack healthy cells to produce multiple copies of themselves. The body’s natural response is to take a sliver of that virus to the surface of the cell and expose it to immune-system warrior cells.

“It basically acts as a fire alarm and says, ‘Hey, look at me guys. I’m infected with a foreign material, do something about it,’ ’’ said Paul de Bakker, a geneticist at the Broad.

The genetic testing found something distinctive about that warning system in controllers — differences in five amino acids, which are the building blocks of proteins. In those people, a tiny groove in a molecule that is part of the warning system has a particular shape, affecting how the warning flag sits atop cells.

“A handful of amino acids doesn’t sound like a huge change,’’ de Bakker said. “But the impact of those protein changes may make a huge difference in an individual’s ability to naturally control HIV.’’

Barry Greenfield figures he caught the virus in the 1970s. He tested positive in the ’80s. He watched friend after friend die, but he has never had a single symptom associated with HIV. Not one.

Now 64 years old, he has traveled to Boston from his home near Los Angeles three times to have blood drawn and biopsies performed for the study.

“My community was decimated, and I got to live and am in a very special place in history where my body has some of the answers,’’ Greenfield said. “I owe it.’’

Small Protein Changes May Make Big Difference in Natural HIV Control. 4/11/10

Handful of nucleotides make the difference between those who can stay healthy and those who, without treatment, will develop AIDS

Tiny variants in a protein that alerts the immune system to the presence of infection may underlie the rare ability of some individuals to control HIV infection without the need for medications. In a report that will appear in Science and is receiving early online release, an international research team led by investigators from the Ragon Institute of Massachusetts General Hospital (MGH), MIT and Harvard and from the Broad Institute of MIT and Harvard describe finding that differences in five amino acids in a protein called HLA-B are associated with whether or not HIV-infected individuals can control viral levels with their immune system only.

"We found that, of the three billion nucleotides in the human genome, just a handful make the difference between those who can stay healthy in spite of HIV infection and those who, without treatment, will develop AIDS," says Bruce Walker, MD, director of the Ragon Institute and co-senior author of the Science article. "Understanding where this difference occurs allows us to sharpen the focus of our efforts to ultimately harness the immune system to defend against HIV."

"Earlier studies had showed that certain genes involved with the HLA system were important for HIV control," adds Paul de Bakker, PhD, of the Broad Institute and Brigham and Women's Hospital, co-senior author. "But they couldn't tell us exactly which genes were involved and how they produced this difference. Our findings take us not only to a specific protein, but to a part of that protein that is essential to its function."

It has been known for almost two decades that a small minority -- about one in 300 -- of individuals infected with HIV are naturally able to suppress viral replication with their immune system, keeping viral load at extremely low levels. To identify genetic differences that may underlie this rare ability, Florencia Pereyra, MD, at the Ragon Institute established the International HIV Controllers Study in 2006, with a goal of enrolling 1,000 HIV controllers from medical clinics and research institutes around the world. That goal was expanded to 2,000 controllers in 2008, and thus far over 1,500 controllers have been enrolled.

The current investigation began with a genome-wide association study (GWAS) of almost 1,000 controllers and 2,600 individuals with progressive HIV infection, through a collaboration with the AIDS Clinical Trials Group. The GWAS, which tests variations at a million points in the human genome, identified some 300 sites that were statistically associated with immune control of HIV, all in regions of chromosome 6 that code for HLA proteins. Further analysis narrowed the number of gene sites to four but could not indicate whether those differences actually affected viral control or were just located near the causal variants. Fully sequencing that genome region in all participants was not feasible, but a process developed by Sherman Jia -- a medical student in the Harvard-MIT Health Sciences and Technology program, working with de Bakker at the Broad -- pinpointed specific amino acids; and directly testing those sites associated five amino acids in the HLA-B protein with differences in viral control.

HLA-B is essential to the process by which the immune system recognizes and destroys virus-infected cells. Usually HLA-B grabs onto viral protein segments called peptides that are inside the cell and carries them to the cell membrane where they essentially flag the infected cell for destruction by CD8 "killer" T cells. The portion of the HLA-B protein that grabs and displays viral peptides is called the binding pocket, and all of the five identified amino acid sites are in the lining of the binding pocket.

"Amino acid variation within the HLA-B binding pocket will impact its shape and structure, probably resulting in some peptides being presented effectively and others not," de Bakker says. "Our work demonstrates that these variants could make a crucial difference in the individual's ability to control HIV by changing how HLA-B presents peptides from this virus to the immune system."

Walker adds, "HIV is slowly revealing its secrets, and this is yet another. Knowing how an effective immune response against HIV is generated is an important step toward replicating that response with a vaccine. We have a long way to go before translating this into a treatment for infected patients and a vaccine to prevent infection, but we are an important step closer."

The investigators note that these findings would not have been possible without the participation of the hundreds of HIV controllers, many of whom traveled to Boston for testing, who have enrolled in the study. "The enthusiasm among the patients we have enrolled and the HIV providers who referred them has been amazing," says Pereyra. "They tell us that being part of this collaborative study means a lot to them."

Original support for the International HIV Controllers study came through a 2006 grant from the Mark and Lisa Schwartz Foundation, and the study was expanded in 2008 through the support of the Bill and Melinda Gates Foundation. Additional supporting agencies include the Harvard Center for AIDS Research and the National Institutes of Health.

Walker is a professor and de Bakker an assistant professor of Medicine at Harvard Medical School. Under the leadership of Pereyra, more than 300 investigators at over 200 institutions around the world contributed to the Science study. Study co-authors include, among others, Steven Deeks, MD, University of California, San Francisco; Amalio Telenti, MD, PhD, University of Lausanne, Switzerland; Mary Carrington, PhD, National Institutes of Health; Vincent Marconi, MD, Emory University; David Haas, MD, Vanderbilt University; John Fangman, MD, AIDS Resource Center of Wisconsin: Martin Markowitz, MD, Aaron Diamond AIDS Research Center; Richard Harrigan, PhD, British Columbia Centre for Excellence in HIV/AIDS; James Braun, DO, Physicians Research Network, New York; Ronald Nahass, MD, I.D. Care Associates, Hillsborough, New Jersey: and Otto O. Yang, MD, University of California. Los Angeles.

Natural Immunity and HIV. 19/10/10

Repeatedly exposed to HIV but remain seronegative

POZ

A current supplement to the Journal of Infectious Diseases is devoted to natural immunity to HIV infection.

It's focus is on individuals who have been repeatedly exposed to HIV but remain seronegative. Several different genetic and immunological mechanisms have already been discovered that can account for their apparent resistance to infection.   The best known may be the inherited absence of a particular cell surface molecule that HIV needs in order to infect a cell as a result of a genetic mutation (CCR5delta32).  

Gene Shearer, a pioneer in the study of HIV exposed seronegative individuals published some of the earliest reports on this phenomenon. In this journal supplement he with Mario Clerici estimate that about 10 - 15 % of individuals repeatedly exposed to HIV remain uninfected.

They note that in the first years of the epidemic "little attention was given to the chance observation that mucosal [or] parenteral exposure to human immunodeficiency virus type 1 (HIV) would not consistently induce infection, and none to the possibility that such putative non-infectious exposures might induce protective immunity ". 

I can't recall that there ever was an assumption that mucosal or parenteral exposure to HIV would consistently induce infection.   This would have accorded HIV the probably unique ability among infectious agents to infect 100% of those exposed to it.      However I certainly recall that in the earliest years after HIV was discovered it was assumed that infection would invariably lead to disease.  HIV infection, it was claimed was like a Mack truck with nothing but time standing in the way of its inevitable progression to disease. This too would have made HIV infection almost unique among infectious diseases. Rabies may be the only infectious disease where 100% of infected (and unvaccinated) individuals become ill, although I believe some exceptions have been described. 

The rapid acceptance of the assumption that HIV infection always leads to disease was quite remarkable at that time, as there could not yet have been sufficient observations to justify ascribing such an unusual property to HIV infection.    Yet this view was so firmly held by the HIV research leadership that it was left to AIDS activists to alert them in the 1990s (1) to the fact that there were indeed individuals who appeared not to have progressive disease, or whose disease progressed very slowly.  

By 1981 we had come to understand that infection and disease are not synonymous terms. But it almost seemed that this important lesson learned at least a century ago had somehow been ignored by some of those producing a detailed picture of the course of HIV infection at a time when so little was known about it.  

These words were written by Rene Dubos, a great microbiologist, in "Man Adapting" published in 1966.   

".......this approach requires that the determinants of infection be separated conceptually from the determinants of disease; its objective will be to understand and control the processes responsible for converting infection into overt disease"

That there is a distinction between infection and disease is something I learned as a medical student in Johannesburg in the 1950s which I in turn tried to pass on when I taught medical students in New York in the late 1960s until 1977.    Even in the first years of the epidemic I sent copies of Man Adapting to several individuals involved in the early response as I was discovering with surprise that some concepts that I thought were firmly established in our understanding of infectious diseases seemed all too frequently to have been forgotten.   

Rene Dubos, was associated with the Rockefeller University in New York for 50 years. He was a towering figure.  His writings helped move us beyond the oversimplification that is the germ theory of disease. 

While recognizing that the doctrine of specific etiology - as represented by the germ theory of disease was "the most powerful single force in the development of medicine", he also wrote that "there is now increasing awareness that it fails to provide a complete account of most disease problems as they naturally occur".

Rene Dubos died in 1982, one year after AIDS was first recognized. The "now" in the above quotation refers to a period before 1966, when "Man Adapting" was published. The increasing awareness of the limitations of the doctrine of specific etiology had apparently dissipated by 1981, at least in the medical response to AIDS.   At that time, genetic factors, socio- economic factors, behavioral factors, the effect of concurrent infections, or anything else were not going to slow the Mack truck.  By 1990, only six years after HIV had been discovered we were also told that, except for a period of 3 to 6 months after infection, called the window period, tests for HIV antibodies could not fail to detect infection.

But reality cannot be held at bay indefinitely, and to the surprise of some there did indeed appear to be individuals who were HIV infected but were able to control the infection to varying degrees, as well as those who were infected for prolonged periods but had no detectable antibodies.    However when the first reports of these phenomena appeared, the authors were subjected to a torrent of outraged criticism, much of it abusive.

David Imigawa and The Window Period.

In 1989 David Imagawa, reported that in 31 of 133 HIV antibody negative individuals it was possible to detect the presence of the virus (2) for periods longer than 6 months. In 27 of these individuals, HIV continued to be detected for up to 36 months despite remaining HIV antibody negative.   This publication in the New England Journal of Medicine resulted in a furious response culminating in a letter to the New England Journal of medicine from David Imagawa and Roger Detels that almost appeared to be a retraction but certainly was not. 

David Imagawa and his colleagues were subjected to hostile and baseless criticism, not only from leading researchers but also from journalists.

This is the headline of a story in the New York Times in 1991 which will give some idea of the kind of response the report received.

THE DOCTOR'S WORLD; Researchers in Furor Over AIDS Say They Can't Reproduce Results.

This is how the article starts:

"THE scientists who came up with one of the most shocking scientific findings about AIDS -- one that set off alarms concerning the safety of the blood supply and about the state of mind of people at risk -- now cannot reproduce their own results. But they still have not said clearly that their finding was incorrect".

It includes this statement:

"Even this confusing letter would not have appeared without constant pressure behind the scenes from officials of the National Institutes of Health who paid for the original research and who were determined to try to straighten the record".

But how secure was the record from which David Imagawa and Roger Detels had strayed? 

 In 1989, only 5 years after the discovery of HIV, with the relatively little experience that had then accumulated, we could only be at a stage of establishing a record.   There was no firmly established record at that time when activists had yet to alert officials that long term non progressors really existed.

Whatever attributes science possesses that distinguishes it from more metaphysical pursuits surely one is a requirement to as best as we can describe phenomena as they are, rather than as we might wish to see them. 

The constant behind the scenes pressure exerted on David Imagawa noted by the New York Times seems more like demands made on an apostate to recant.   

David Imagawa's observations were in fact correct.  Similar observations have been made by others.

Sadly he did not live to experience the vindication of his pioneering studies. He died of a heart attack shortly after the New York Times article appeared.

A fairly detailed account of the course of HIV infection had been constructed only 5 to 6 years after the discovery of HIV that had no place for prolonged seronegative infection. This account is illustrated in the very familiar diagram of the typical course of HIV infection that appeared in the 1990s.

The rapid acceptance in those early years that there even was a typical course of HIV infection is particularly odd as not only was the disease newly recognized, we then had no precedents of human retroviral diseases (apart from HTLV-1 associated disease);  the techniques used to study the disease were themselves new. The ability to identify T lymphocyte subsets with monoclonal antibodies is about as old as the HIV epidemic. So we had no idea at that time of the variation in T subset numbers in health and disease. Other new immunological and virological techniques were, and continueto be introduced.   

At that time, only 5 to 6 years after the discovery of HIV there could not have been a solid enough empirical foundation to justify the confident assertion, in the case of sexually transmitted HIV that there could not be situations where integrated HIV DNA is carried for prolonged periods without seroconversion. Unlike infections acquired by blood or blood products, the time of initial infection can rarely be known. The infecting dose of virus in the case of sexual transmission could be even orders of magnitude less than that when infection is acquired by blood transfusion. 

How then to account for the persistence of recoverable virus for up to 36 months in the absence of seroconversion?      

In the original New England Journal of Medicine publication David Imagawa and his colleagues raised the possibility of  "silent" HIV infection, suggesting that HIV in the form of proviral DNA integrated into the genome could persist without production of HIV virions.  This is a perfectly reasonable suggestion. 

But in their subsequent letter, they changed their minds and ascribed their finding to the ability of the men to overcome the infection. Because of continued high risk activity virus was repeatedly detectable.   In a more recent article Roger Detels expands on this explanation, noting: "The fact that we isolated HIV ONLY from those men who continued their high-risk exposure suggested that transient infection and clearance of HIV was the more likely explanation".

Of course this may be the explanation.  If so, HIV sequences should have been consistent on repeated isolations, whereas if infections were transient, variations would surely have been seen between repeated isolates. This is because HIV, when it is in the form of DNA, remains unchanged.  Sequence variations between different virus isolations may have been reported somewhere.

But in another report of prolonged carriage of HIV DNA in seronegative individuals, sequences remained constant (3). In the abstract of this paper the authors note: (ES refers to exposed seronegative individuals)

"Some individuals remain inexplicably seronegative and lack evidence for human immunodeficiency virus type 1 (HIV-1) infection by conventional serologic or virologic testing despite repeated high-risk virus exposures. Here, we examined 10 exposed seronegative (ES) individuals exhibiting HIV-1-specificcytotoxicity for the presence of HIV-1. We discovered HIV-1 DNA in resting CD4(+) T cells (mean, 0.05 + /- 0.01 copies per million cells) at multiple visits spanning 69 to 130 weeks in two ES individuals at levels that were on average 10(4)-to 10(6)-fold lower than those of other HIV-1-infected populations reported. Sequences of HIV-1 envelope and gag genes remained markedly homogeneous, indicating little to undetectable virus replication. These results provide the evidence ......... suggesting that extraordinary control of infection can occur. The two HIV- infected ES individuals remained healthy and were not superinfected with other HIV-1strains despite continued high-risk sexual exposures to multiple HIV-infected partners. Understanding the mechanisms that confer diminished replicative capacity of HIV-1 in these hosts is paramount to developing strategies for protection against and control of HIV-1 infection".

At the heart of the furious response to David Imagawa's observation was the fear it might have raised about the safety of the blood supply and the peace of mind of those testing HIV negative. Roger Detels in the article linked to above makes these comments:

As far as the blood supply is concerned, the most reliable data on the window period were derived from observations on transfusion related infections, and antibody tests have been hugely effective in ensuring the safety of the blood supply (even without additional tests reducing the risk to less than 1 in 1,000,000).   So the New York Times article and others like it were quite unjustified in raising fears for the safety of transfused blood based on observations made on sexual transmission. 

As far as the peace of mind of individuals testing negative is concerned, if there should be those who are able to maintain HIV in latency in the form of proviral DNA, that is never fully expressed, it's entirely possible that in some of these individuals, HIV has had an immunizing effect rather than causing productive infection. 

It appears that to this day the reluctance to even consider HIV seronegative infection persists.

Returning to the supplement of the Journal of Infectious Diseases dealing with natural immunity to HIV, the possibility of stable HIV infections that remain unexpressed is not considered at all as at least one explanation for the continued absence of antibodies in some individuals exposed to HIV.   It seems to be just taken for granted that these individuals are resistant to infection.  

We are told:

Approximately 15% of HIV exposed seronegative individuals repeatedly resist infection, a phenomenon that has been observed in all investigated HIV‐exposed cohorts. 

But how can it be known that all of these seronegative individuals exposed to HIV have resisted infection?   Some may carry HIV in the form of unexpressed proviral DNA.   Even if this is not detected in cells circulating in the blood stream this does not mean a great deal as only a tiny minority of CD4 + cells circulate, and the DNA containing HIV may be in cells without the CD4 receptor.

If HIV can be carried in a stable integrated form as proviral DNA, that is not expressed at all or only partially and intermittently expressed, then this may be the basis for the apparent resistance of some ESNs. Such an individual would  not be resistant to infection, but for probably a variety of reasons connected both with the virus, as well as the host, infection is aborted at the stage of integration. 

 We know some of the signals that can activate HIV DNA to start the process of making new viral particles. Some cytokines are potent activators of HIV and can also appear during the course of other infections.    In the absence of sustained activating signals and with a small infecting dose of virus abortive but persistent infection might occur. If there is very limited viral replication this may be sufficient to induce a cell mediated immune response, ensuring that cells expressing HIV antigens are killed, as is the case with EBV infected B lymphocytes.

HIV infection, like other chronic viral infections can progress in different ways.  If we had been more open to this, rather than trying to discourage work that did not conform to the early preconceptions about the course of HIV disease  there may have been greater interest and funding into research that investigates the various factors that influence how the disease progresses.

Inflammatory Proteins in Blood Predict HIV Death Risk. 18/10/10

Chronic inflammation is common in people with HIV

HIV-positive people who have elevated levels of two blood inflammatory proteins, fibrinogen and high sensitivity C-reactive protein (hsCRP), have a higher risk for premature death than people with lower levels of the two proteins, according to a study published in the November 1 issue of the

Inflammation is a normal process that occurs in the body in response to infection and to damaged or defective cells. In fact, the symptoms of the flu or common cold—fever, achiness, swollen glands—are all related to inflammation. When inflammation becomes chronic, however, vital organ systems, such as the blood vessels, heart, kidneys and liver, can become damaged, which ultimately increases the risk of serious health problems and death.

Researchers are finding growing evidence that chronic inflammation is common in people with HIV, and that HIV itself may be driving chronic inflammation. To shed further light on this topic, Phyllis Tien, MD, from the University of California at San Francisco, and her colleagues examined stored blood samples from the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study. The FRAM study ran from 2000 to 2002 and was designed to study lipodystrophy in 1,183 HIV-positive people

In the current study, Tien’s team tested the blood samples for levels of fibrinogen and hsCRP and studied whether increased levels of these inflammatory markers predicted early mortality. To accomplish this, the team segmented the study participants based on both their fibrinogen levels and their hsCRP levels: in each case, those with the highest levels were grouped together, as were those with the lowest levels and those with moderate levels.

Tien and her colleagues found that both inflammatory proteins were highly significant as independent predictors of premature death—over and above other cardiovascular and HIV disease risk factors. People with the highest fibrinogen levels were more than three times as likely to die prematurely as those with the lowest levels. People with the highest hsCRP levels were nearly four times as likely to die early. Researchers also noted a trend suggesting that people with high levels of both proteins had poorer survival than people with high levels of only one protein, but the difference was small enough that it could have occurred by chance

Tien and her team also segmented the results based on CD4 count. They did find that people with lower CD4s were more likely to have high fibrinogen levels and to die than people with high CD4s. The authors also found, however, that high fibrinogen levels were tied to an increased premature death risk even in people with CD4 counts over 500.

The authors caution that it is too early to suggest using either of these inflammatory markers as a means to predict which HIV-positive people might be most at risk for illness and death. They state, however, that these results do support the notion that inflammation is a driving force in illness and death in people with HIV.

Ongoing studies are testing whether common medications, such as aspirin and cholesterol-lowering statins, can lower inflammation in people with HIV. To that end, the authors conclude: “Investigation is needed to determine whether interventions to reduce fibrinogen and CRP levels might decrease mortality risk in HIV-infected individuals.”

New Look at Multitalented Protein Sheds Light on Mysteries of HIV. 14/10/10

Scientists have glimpsed an important protein molecule's behavior with unprecedented clarity.

New insights into the human immunodeficiency virus (HIV) infection process, which leads to acquired immunodeficiency syndrome (AIDS), may now be possible through a research method recently developed in part at the National Institute of Standards and Technology (NIST), where scientists have glimpsed an important protein molecule's behavior with unprecedented clarity.

The HIV protein, known as Gag, plays several critical roles in the assembly of the human immunodeficiency virus in a host cell, but persistent difficulties with imaging Gag in a lab setting have stymied researchers' efforts to study how it functions.

"A better understanding of Gag's behavior might allow researchers to develop antiviral drugs that target the HIV assembly process, which remains unassailed by medical science," says Hirsh Nanda, a postdoctoral researcher at the NIST Center for Neutron Research (NCNR) and a member of the multi-institutional research team. "Our method might reveal how to inhibit new viruses as they grow."

The Gag molecule is a microscopic gymnast. At different stages during HIV assembly, the protein twists itself into several different shapes inside a host cell. One shape, or conformation, helps it to drag a piece of HIV genetic material toward the cell membrane, where the viral particles grow. Gag's opposite end becomes anchored there, stretching the protein into a rod-like conformation that eventually helps form a barrier surrounding the infectious genes in the finished virus. But while scientists have been aware for years that Gag appears to play several roles in HIV assembly, the specifics have remained mysterious.

The research team potentially solved this problem by creating an artificial cell membrane where Gag can show off its gymnastic prowess for the neutron probes at the NCNR. The center includes a variety of instruments specifically designed to observe large organic molecules like proteins.

"We were able to mimic the different stages of the virus's development, and look at what Gag's conformation was at these various stages," Nanda says. "We saw conformations that had never been seen before."

Nanda describes the team's first paper* on the subject as an important first step in describing their observational method, which was a joint effort between NIST, the National Cancer Institute and Carnegie-Mellon University. They plan another paper detailing what the method has revealed about HIV.

"Our efforts have not yet shown us how many steps are involved in Gag's work assembling an HIV particle, but at least we can see what it looks like in each major interaction that likely occurs in the cell during assembly," Nanda says. "It may allow us to characterize them for the first time."

Nanda says that their technique will also allow scientists to examine large classes of membrane proteins, which like Gag are notoriously hard to examine.

Rare Hybrid Cell Key to Regulating the Immune System. 11/10/10

A cell small in number but powerful in its ability to switch the immune system on or of

A cell small in number but powerful in its ability to switch the immune system on or off is a unique hybrid of two well-known immune cell types, Medical College of Georgia researchers report.

The discovery of this rare hybrid could have implications for the efficacy of new therapies that manipulate these two cell types to treat diseases such as cancer and rheumatoid arthritis.

When MCG scientists first reported the human equivalent of this cell in Science in 2002, they called it a subset of the dendritic cell that clusters in high exposure areas such as the gut but also roams the body, looking for invaders like a virus or cancer. Dendritic cells show their find to T cells, telling them to ignore or attack by bringing trash-eating macrophages, natural killer cells and the like into the fight.

What seemed most unique about the subset is its ability to express indoleamine 2,3 dioxygenase, or IDO, to turn off T cells. IDO is an enzyme used by fetuses and tumors alike to escape the immune response.

The new studies show that is only part of the cells' distinctiveness. The cells also have the identifying markings of B cells, known for their ability to make antibodies against invaders. In fact, they found the IDO-presenting cells came from the same precursor cell as B cells. But, when the scientists looked at mice missing B cells, they still found the IDO-producing cells. Hence, the cell didn't need to produce antibodies to turn off T cells.

In reality, IDO-expressing cells have properties of both cells, said Burles A. Johnson III, an MCG M.D.-Ph.D. student and first author of the paper published in the Proceedings of the National Academy of Sciences. "It looks like a B cell and it's not. It looks like a dendritic cell and it is and it isn't," Johnson said.

While their studies are in mice, the cells also are in humans, showing up in some unfortunate places such as the drainage system for tumors, melanoma or even HIV where they likely help the diseases survive.

They also may be showing up in new dendritic cell therapies designed to strengthen the immune response to cancer. If the therapies happen to include some IDO-expressing cells, those could end up helping the cancer, said Mellor, the paper's corresponding author. "All you need is a few of these cells in your dendritic cell vaccine and you don't get stimulation any more, you get suppression," Mellor said.

Their confusing face could also cause hybrids to be lost in B cell-depleting therapies designed to lessen the immune system's attack on joints in rheumatoid arthritis. "These therapies may also deplete IDO-expressing cells and decrease therapy effectiveness because you are eliminating cells that are there to help you," Johnson said.

"This gives us new insight into why these therapies might not be working as well as we think they might," Mellor added. Long-term goals include figuring out how to manipulate the hybrid's activity to benefit patients.

The research was funded by the National Institutes of Health and the Germany-based pharmaceutical company Boehringer-Ingelheim. Mellor is a Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics.

Study Details Structure of Potential Target for HIV and Cancer Drugs. 11/10/10

CXCR4 can spur the growth and spread of cancer cells

In a technical tour de force, structural biologists funded by the National Institutes of Health have determined the three-dimensional structure of a molecule involved in HIV infection and in many forms of cancer. The high-resolution structure sheds light on how the molecule functions and could point to ways to control its activity, potentially locking out HIV and stalling cancer's spread.

The molecule, CXCR4, is part of a large family of proteins called G-protein coupled receptors (GPCRs). These molecules span the cell's membrane and transmit signals from the external environment to the cell's interior. GPCRs help control practically every bodily process, including cell growth, hormone secretion and light perception. Nearly half of all drugs on the market target these receptors.

"Scientists have been studying CXCR4 for years but have only been able to guess at what it looks like," said NIH Director Francis S. Collins, M.D., Ph.D. "Now that we have its structure, we have a much clearer picture of how this medically important molecule works, opening up entire new areas for drug discovery."

The researchers, led by Raymond C. Stevens, Ph.D., of the Scripps Research Institute in La Jolla, Calif., report their findings in the Oct. 7, 2010, advance online issue of the journal Science. The study received support from two major NIH initiatives: the structural biology program of the NIH Common Fund and the Protein Structure Initiative (PSI).

While a molecule called CD4 is the primary receptor for HIV, CD4 is not sufficient for the virus to penetrate cells. In 1996, a team of researchers at NIH's National Institute of Allergy and Infectious Diseases (NIAID) discovered that CXCR4 acts as a co-receptor by helping HIV enter cells.

Normally, CXCR4 helps activate the immune system and stimulate cell movement. But when the signals that activate the receptor aren't properly regulated, CXCR4 can spur the growth and spread of cancer cells. To date, CXCR4 has been linked to more than 20 types of cancer.

The Scripps Research scientists set out to shed light on how CXCR4 functions by capturing snapshots of the protein by using a structure determination method called X-ray crystallography. To understand how natural molecules might bind and signal through the receptor and to see how potential drugs could interact with it, they examined CXCR4 bound to known inhibitors of its activity.

Determining the structure of CXCR4 represented a major challenge because membrane proteins are notoriously tricky to coax into the crystal form required for the X-ray technique. After three years of optimizing conditions for producing, stabilizing and crystallizing the molecule, the scientists finally generated five distinct structures of CXCR4.

The structures showed that CXCR4 molecules form closely linked pairs, confirming data from other experiments indicating that pairing plays a role in the proper functioning of the receptor. With this knowledge, scientists can delve into how the duos might regulate CXCR4's activity and better understand how CXCR4 functions under normal and disease conditions.

The images also showed that CXCR4 is shaped like two white wine glasses touching in a toast, with the inhibitors bound at the sides of the bowls. By detailing these contacts, the researchers said the pictures suggest how to design compounds that regulate CXCR4 activity or block HIV entry into cells. If developed into drugs, such compounds could offer new ways to treat HIV infection or cancer.

"An approach to determining protein structures that was developed with support from the NIH Common Fund and the PSI is now paying huge dividends," said Jeremy M. Berg, Ph.D., director of the National Institute of General Medical Sciences, which supports the PSI. "It illustrates how technical progress provides a foundation for rapid advances, and it also showcases the benefits of collaborations between structural biologists and scientists working in other fields for addressing fundamentally important problems with tremendous potential for medical applications."

New Computer Modelling System Predicts Responses to HIV and AIDS Treatments. 7/10/10

The system predicts how the patient will respond to hundreds of alternative combinations of HIV drugs.

A new system for predicting how individual patients with HIV and AIDS will respond to different drugs is launched October 6 by RDI, a UK-based not-for-profit research group. The experimental system, called the HIV Treatment Response Prediction System (HIV-TRePS), is available free of charge over the Internet and helps physicians select the best treatment for their patients.

HIV-TRePS harnesses the power of complex computer models that have been trained with data from tens of thousands of patients treated in hospitals around the world. Physicians access the system over the Internet and enter their patient's data, and the system predicts how the patient will respond to hundreds of alternative combinations of HIV drugs. Within seconds, the physician receives a report listing the drug combinations that the models predict are most likely to work.

Studies conducted by the RDI and its partners have demonstrated that the system can potentially improve patient outcomes and reduce the overall number -- and therefore cost -- of drugs used.

"This is a very exciting development -- the system literally puts the experience of treating thousands of different patients at the doctor's fingertips," commented Dr. Julio Montaner, Past President of the International AIDS Society and Director of the BC Centre for Excellence in HIV & AIDS, based in Vancouver, Canada. "This has the potential to improve outcomes for people living with HIV and AIDS around the world, particularly where resources and expertise are scarce."

Selecting and changing treatments for patients with HIV and AIDS in order to keep the virus suppressed is complex and challenging. There are approximately 25 HIV drugs available, from which physicians normally choose a combination of three or more to suppress the virus. However, mutations occurring in the viral genetic code can cause resistance to the drugs used against it. The physician then has to select a new combination of drugs to overcome this resistant strain.

The computational models within HIV-TRePS, called "Random Forests," base their predictions on a range of more than 80 different variables including mutations in the viral genetic code, the drugs used to treat the patient in the past, CD4 cell counts (a type of white blood cell that is attacked by HIV) and the amount of virus in the bloodstream. The models estimate the probability of each combination of drugs reducing the amount of virus to below the limit of detection in the blood (50 copies HIV RNA/ml) based on what the system has 'learnt' during its training with thousands of real clinical cases. The system's overall accuracy during development and testing was approximately 80%.

The easy-to-use system has proven to be a significantly more accurate predictor of response than genotyping with rules-based interpretation -- a test that is commonly used today to help drug selection.

"We are really excited about the launch of this system, which is a milestone for us, our research partners around the world and also for the use of bioinformatics in medicine," said Dr Brendan Larder, Scientific Chair of the HIV Resistance Response Database Initiative (RDI). "We believe this approach can make a significant difference in a variety of settings and diseases."

The RDI is already working on a version of HIV-TRePS for use in resource-limited settings where there are fewer treatment options and health care workers do not have access to all the information that this initial system requires. The RDI's approach could also have potential benefit in other diseases, most obviously where drug resistance can be a problem such as Hepatitis.

Infectious and Non-infectious Lung Disease Risk Increased for those with HIV. 29/9/10

HIV is associated with an increased risk of lung disease with infectious and non-infectious causes

AIDSMap

HIV is associated with an increased risk of lung disease with infectious and non-infectious causes, US investigators report in the American Journal of Respiratory and Critical Care Medicine.

The study was conducted in the era of modern antiretroviral treatment, and bacterial pneumonia and chronic obstructive pulmonary disease were the most common lung diseases seen in patients with HIV.

The investigators found evidence that a higher CD4 cell count, a low viral load and taking HIV treatment were protective against lung disease, even some that did not have an infectious cause.

There was also evidence that older age increased the risk of pulmonary complications, adding lung conditions to the diseases of ageing that are of concern for people with HIV.

In the era before effective antiretroviral treatment was introduced, lung disease was an important cause of serious illness and death in people with HIV. Some research suggests that individuals with HIV continue to have an increased risk of lung problems, including those with non-infectious causes.

Investigators from the US Department of Veterans’ Affairs wished to gain a better understanding of the risks of pulmonary complications for patients with HIV. They therefore compared the incidence of diseases with infectious and non-infectious causes between 33,420 HIV-positive patients and 66, 840 HIV-negative individuals. Analyses were also performed to see if any specific factors were associated with lung disease for those with HIV.

Both groups were well matched demographically. The median age was 45, the overwhelming majority were male, and over 40% were African American.

Prevalence of alcohol abuse (21% vs. 19%), drug use (23% vs. 15%) and hepatitis C infection (30% vs. 11%) was higher amongst those with HIV. In addition, patients with HIV were significantly more likely to smoke (80% vs. 76%, p < 0.001).

At baseline, the patients with HIV had a median CD4 cell count of 264 cells/mm³ and two-thirds were taking antiretroviral therapy.

On entry to the study, 7% of those with HIV and 6% of HIV-negative patients had one or more pulmonary conditions. This difference was significant (p < 0.01). Patients with HIV were more likely to have lung disease with infectious and un-infectious causes.

HIV-positive patients were significantly more likely to develop new lung diseases. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common conditions. The incidence of bacterial pneumonia was 28 per 1000 person years among those with HIV compared to 6 per 1000 person years for HUIV-negative patients (p < 0.001). Similarly, incidence of chronic obstructive pulmonary disease was also markedly higher among patients with HIV (23 vs. 17 cases per 1000 person years, p < 0.001).

Although quite rare, lung cancer, pulmonary hypertension and pulmonary fibrosis were all significantly more likely to occur in those with HIV (all p < 0.001).

Unsurprisingly, patients with HIV also had higher incidence rates of PCP pneumonia and tuberculosis.

With the exception of PCP and asthma, the incidence of all pulmonary disease increased with age. This was true for both HIV-positive and HIV-negative patients.

The investigators calculated that even after adjusting for smoking, those with HIV had an increased risk of developing every kind of pulmonary disease with the exception of asthma.

Attention was then focused on the factors that increased the risk of lung disease for patients with HIV.

A higher CD4 cell count and a viral load below 400 copies/ml was associated with a lower risk of diseases with infectious causes such as bacterial pneumonia, PCP and tuberculosis.

In addition, incidence of chronic obstructive pulmonary disease and asthma was significantly lower in patients taking HIV treatment, with an undetectable viral load reducing the risk of obstructive disease.

“We found that HIV-infected patients were more likely to have incident diagnoses of non-infectious chronic diseases including…as well as pulmonary infections”, comment the investigators.

“Fewer infectious complications and a greater frequency of non-HIV associated pulmonary disease…appears to parallel the greater burden of chronic, non-infectious comorbid diseases afflicting many aging HIV-infected patients”, they add.

The investigators suggest that HIV specialists should be mindful of their findings when providing care to their patients.

Microbiologists Find Source of Fungus’s Damaging Growth. 24/9/10

Fungus kills more than 10,000 people with weakened immune systems each year

Candida albicans, a fungus that kills more than 10,000 people with weakened immune systems each year, grows more dangerous as it forms and extends long strands of cells called hyphal filaments. In a paper published this month, UT Health Science Center San Antonio microbiologists describe a key factor involved in this damaging growth.

This finding may eventually lead to targets for antifungal strategies, the scientists said.

Patricia Carlisle, a Ph.D. student at the Health Science Center, and David Kadosh, Ph.D., assistant professor of microbiology, found that Ume6, a key transcriptional regulator, targets a specific hyphal filament-development mechanism. "No one knew that Ume6 was involved in directing this process," Dr. Kadosh said. "Perhaps we can learn how to mute its signals."

Transcriptional regulators direct the conversion of DNA (deoxyribonucleic acid) into RNA copies. Copies of RNA (ribonucleic acid) are translated into proteins that carry out activity.

Bug's impact

Candida albicans preys on hospitalized critical care patients, HIV/AIDS patients, cancer patients and others with weakened immune systems. It is the fourth-leading cause of hospital-acquired infections in the United States.

"The forming of hyphal filaments is very important in tissue invasion and other activities," Dr. Kadosh said.

The findings were featured as a Spotlight article in the September issue of Eukaryotic Cell, a journal of the American Society for Microbiology.

FTC Therapy Reduces Risk of Important Resistance Mutation. 23/9/10

FTC and tenofovir reduces resistance mutation

AIDSMap

The important M184V resistance mutation is less likely to emerge if a patient is receiving an HIV treatment combination that includes FTC and tenofovir rather than a combination that contains 3TC, an international team of investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

The study also showed that treatment with a boosted protease inhibitor was protective against the emergence of the M184V mutation and that the combination of FTC and tenofovir had a high genetic barrier to resistance.

The investigators believe that the study’s “overall findings highlight the importance to identify those drug combinations that can minimize drug resistance to HAART [highly active antiretroviral therapy]. Understanding the point is crucial to maximize the opportunity for successful and subsequent therapies after viral rebound not only in western countries but also in resource-limited settings.”

Thanks to antiretroviral therapy, many patients with HIV now have a near normal prognosis. However, the emergence of drug resistance can mean that the potential benefits of treatment are reduced. Understanding the factors that can reduce the risk of resistance is therefore important.

Recent research suggests that the risk of resistance is reduced if a patient is taking a ritonavir-boosted protease inhibitor. In addition, treatment with FTC (emtricitabine, Emtriva, also in the combination pills Truvada and Atripla) appears to be less likely to result in resistance than therapy with 3TC (lamivudine, Epivir, also in the combination pills Combivir and Trizivir).

An international team of investigators wished to gain a better understanding of the risk of the M184V resistance mutation in patients taking failing antiretroviral therapy containing FTC and tenofovir compared to combinations containing 3TC and tenofovir, or 3TC with another nucleoside reverse transcriptase inhibitor (NRTI).

A total of 352 patients were included in the study. Of these, 42 were taking FTC and tenofovir, 40  were treated with 3TC plus tenofovir, and 207 with 3TC and another NRTI. None had received these drugs as part of an earlier HIV treatment combination. All the patients had experienced virologic failure (two consecutive viral load measurements above 50 copies/ml) and their characteristics were broadly comparable.

There was a significantly lower prevalence of the M184V mutation in patients taking FTC and tenofovir than in those taking either 3TC and tenofovir or 3TC and another drug (14% vs. 40% vs. 56%, p = 0.01 and p < 0.001).

Subsequent statistical analysis showed that treatment with FTC reduced the risk the M184V mutation by 68% (OR = 0.32; 95% CI, 0.10-0.99, p = 0.04).

Compared to therapy with a non-nucleoside reverse transcriptase inhibitor (NNRTI), treatment with a ritonavir-boosted protease inhibitor was also associated with a lower risk of the M184V mutation (OR = 0.019; 95% CI, 0.10-0.37, p < 0.01). Treatment with tenofovir also reduced this risk (p = 0.05).

Separate test tube analysis showed that HIV infected cell cultures were significantly more likely to be free of the virus when exposed to FTC and tenofovir than after exposure to 3TC and tenofovir (p < 0.0005).

In addition, laboratory analysis suggested that FTC and tenofovir had a higher genetic barrier to resistance.

“This study shows that the use of FTC significantly correlates with a decreased probability of M184V emergence at HAART failure compared with the use of 3TC”, comment the investigators. They add, “the lower prevalence of M184V can be explained by the higher potency of FTC than 3TC”.

Cure for HIV Infection Must Now be Major Scientific Priority, Vienna AIDS Conference Hears. 19/7/10

A cure for HIV infection is scientifically feasible and increasingly necessary

AIDSMap

A cure for HIV infection is scientifically feasible and increasingly necessary, but the goal requires focus and funding, said Sharon Lewin of Monash University in Melbourne, in a keynote address at the opening session of the AIDS 2010 conference and at a preceding workshop organised by the International AIDS Society (IAS).

 Antiretroviral therapy has dramatically reduced illness and increased survival, but people with HIV still do not achieve normal life expectancy relative to the general population, Lewin said. In addition, a growing body of evidence indicates that even very low-level virus contributes to a number of health problems.

The most sensitive tests can find residual HIV in almost everyone infected, including people on effective combination therapy and elite controllers who suppress the virus naturally. "There is no such thing as an undetectable viral load," Lewin added.

As Steven Deeks from the University of California, San Francisco explained at an IAS pre-conference meeting on HIV reservoirs and eradication, these problems – which range from cardiovascular and liver disease to neurocognitive impairment and bone loss – are increasingly linked to chronic immune activation and inflammation triggered by persistent virus.

"There's some sort of HIV-related problem that's causing people to get sick earlier than they otherwise would have," he said.

What's more, long-term antiretroviral therapy for everyone is not sustainable. Lewin noted that even treating the current 40% of HIV-positive people in low- and middle-income countries starting at the old World Health Organization CD4 threshold of 200 cells/mm³ would cost $25 billion by 2030, whilst increasing coverage to 80% would raise that figure to $35 billion.

The main barriers to curing HIV, according to Lewin, are latently infected T-cells, residual viral replication, and anatomical reservoirs (such as the brain, gut and genital tract) that harbour hidden virus.

Most T-cells is the body are resting, she explained. HIV mostly infects active CD4 T-cells, which produce new virus but then soon die. In resting cells, by contrast, HIV genetic material is integrated into the host cell's genome where it can remain dormant for a long time, but can "wake up" at any point and reignite viral replication.

The IAS workshop devoted considerable attention to the ongoing debate about whether problems in people on suppressive antiretroviral therapy are attributable to residual low-level viral replication, re-emergence of latent virus from reactivated T-cells, or a combination of the two.

Scientists do not fully understand how HIV evades the immune response and establishes latency in resting cells, but a variety of signalling molecules and transcription factors appear to play a role, and thus offer potential targets for intervention.

Intensification of antiretroviral therapy by adding more drugs has not been able to eradicate HIV in multiple studies to date. A more promising approach uses agents such as interleukin 7 (IL-7) to activate resting cells and flush HIV out of hiding. Another strategy uses compounds called histone deacetylase (HDAC) inhibitors to turn on HIV genes.

Some two dozen HDAC inhibitors are under study as cancer treatments and one, known as vorinostat or SAHA, is already licensed for T-cell lymphoma. These agents, along with IL-7, appear safe and well-tolerated and should quickly move into clinical trials, Lewin said. She predicted that a combination approach would be most effective.

Daria Hazuda from Merck Research Labs, speaking at the IAS pre-conference meeting, said her company has screened millions of compounds, including numerous HDAC inhibitors, and found several dozen that warrant further study.

Whilst such agents might achieve a 'functional cure' or long-term remission, future approaches could potentially protect cells completely from HIV infection and thereby achieve a 'sterilising cure'.

The experience of one man in Germany, dubbed the 'Berlin patient', offers proof-of-concept that this may be possible. Gero Hütter, who treated the patient, described the case at the IAS pre-conference meeting.

The man underwent chemotherapy for leukaemia that destroyed his own immune cells and received bone marrow stem cell transplants from a donor who carried the protective CCR5-delta32 mutation, which makes cells resistance to HIV infection. Within two months after his first transplant the man showed no measurable HIV, despite stopping antiretroviral therapy. Three years later, he still shows no signs of infection.

While widespread bone marrow transplants are not realistic, Lewin acknowledged, this patient tells us that getting rid of latently infected cells and living without antiretroviral treatment is possible, and we need to learn why. Researchers are now pursuing a related approach, using gene therapy to make cells HIV-resistant.

Lewin urged greater resources for an HIV cure and a collaborative effort of basic scientists, clinicians, pharmaceutical companies and funders, as exists for HIV vaccine research. In recent months, amfAR and the US National Institutes of Health have announced funding for cure research, though advocates argue that it is not sufficient.

"The international conference in Vienna will not be the conference where we announce a cure," Lewin concluded, "but it will mark the beginning of a future where we seriously prioritise finding a cure."

Watch the keynote address from Sharon Lewin on the Kaiser Family Foundation website.

'HIV Cure Still a Long Way'. 26/7/10

Local medical doctors have urged the public not to get too excited yet by the latest research findings on HIV virus

AllAfrica

Oshakati — Local medical doctors have urged the public not to get too excited yet by the latest research findings on HIV virus treatment and preventive measures.

"Such findings remain a research topic. It belongs to the researchers. People in the research set-up could get excited, but it does not excite the people at the clinical part of it, because we know how the HIV virus changes," said Ongwediva Medi-park Director, Tshali Ithete.

Ithete was commenting on findings by federal researchers that came 10 days before the International AIDS Conference in Vienna, Austria. The conference started on July 18 and ended on Friday.

Some of the medical publication websites said researchers have identified a pair of naturally occurring antibodies that are able to kill more than 90 percent of all strains of the AIDS virus, a finding, they say, could lead to the development of new treatment for HIV infections and the production of the first successful vaccine against the virus.

The two antibodies were allegedly discovered in the cells of a 60-year-old African-American gay man, known as Donor 45 by the team of researchers, led by scientists at the National Institute of Allergy and Infectious Diseases (NIAID).

Ithete said finding the vaccine for a certain medical condition is a long process that goes through different stages. Thus researchers are normally cautious whenever they present their findings. He gave an example of some HIV drugs and treatments that were highly publicised, but never saw the light of day, while others never survived the market.

"People should remember how Virodene came in quickly and went. It was still at the research level when it became widely spoken about, but it went before it even got to the manufacturers," said Ithete.

Ithete said the only positive result on the development of HIV treatment and prevention is the development of the microbicide gel.

He said the gel would be helpful, especially to women that are in abusive relationships. "Femidom came and went - finally vulnerable partners have something that can protect them," said Ithete.

He, however, noted that the gel is not 100 percent safe. Therefore, people should concentrate on the existing preventative measures such as condoms.

On the other hand, Dr Bernhard Haufiku said the microbicide gel is not the answer to HIV infections. According to Haufiku, the vaginal gel will not help much in terms of rape and other sexual violence as they happen unpredictably.

"Of course, the gel is one of the prevention measures, but our society has a tendency of relying on new products. Let us stick to the basics. Let us continue with A, B, C and D. If you are HIV-positive take medication (ARVs), as prescribed by the doctor until such time when we, hopefully, find the cure - if it happens to be found during our life- time," said Haufiku.

Haufiku said even if the anti-HIV microbicide gel is a breakthrough to the development of HIV preventative measures, there is still a long way to go before it enters the market.

"It will still get tested and go to the medical authorities, who would see how it can benefit the larger public before it gets approved," he said.

Commenting on the research findings of the antibodies that can allegedly kill 90 percent of HIV strains, Haufiku said the research gives a good prospect for the vaccine and treatment of HIV treatment. However, HIV is a complex disease with complex behaviour. Thus, such findings should not excite the public yet.

AIDS Virus Changes in Semen Make It Different Than in Blood. 20/8/10

HIV may undergo changes in the genital tract

The virus that causes AIDS may undergo changes in the genital tract that make HIV-1 in semen different than what it is in the blood, according to a study led by researchers from the University of North Carolina at Chapel Hill.

Worldwide much of the transmission of HIV-1 is through sexual contact, men being the transmitting partner in a majority of cases. The new findings are significant because the nature of the virus in the male genital tract is of central importance to understanding the transmission process and the selective pressures that may impact the transmitted virus. Ultimately it is the transmitted virus that must be blocked by a vaccine or microbicide.

"If everything we know about HIV is based on the virus that is in the blood, when in fact the virus in the semen can evolve to be different, it may be that we have an incomplete view of what is going on in the transmission of the virus," said senior study author Ronald Swanstrom, PhD, professor of biochemistry and biophysics and of microbiology and immunology at the UNC School of Medicine.

The results of his research appear August 19, 2010 in the online journal PLoS Pathogens.

In the study, Swanstrom and his colleagues compared viral populations in blood and semen samples collected from 16 men with chronic HIV-1 infection. Using an expensive and labor-intensive laboratory technique called single genome sequencing, they analyzed the gene coding for the major surface protein of the virus -- called envelope or Env -- in the samples. The differences between the viruses from the two sources were striking.

"The sequence differences between the blood and the semen were like a flashing red light, it was a big hint about the biology of virus in the seminal tract" said Swanstrom. "When we looked at sequences in the blood, we hardly found any that were the same, it was a very complex and diverse population. But when we looked in the semen, suddenly we were getting the same sequence over and over again."

They found two mechanisms that significantly altered the viral population in the semen, which they called clonal amplification and compartmentalization. In the first, one to several viruses are rapidly expanded over a short period of time such that the viral population is relatively homogeneous (compared to the complex population in the blood). In the second, the virus replicates in T cells in the seminal tract over a long period of time, creating a separate population of virus that is both complex and distinct from the virus in the blood.

To begin to answer why these mechanisms are at play, the researchers measured the levels of 19 cytokines and chemokines in the blood and semen samples. They discovered a significant concentration of these immune system modulators in the semen relative to the blood, which could boost viral replication by creating an environment where target cells are kept in an activated state.

Swanstrom's laboratory is now exploring whether evolutionary selection for some special property of the virus is occurring in the seminal tract that does not happen in the blood. Knowing how the virus in the semen is different is an important part of understanding the HIV transmission puzzle.

The UNC research was funded by the National Institutes of Health in the context of the Center for HIV/AIDS Immunology (CHAVI). Study co-authors include Jeffrey A. Anderson, Li-Hua Ping, Oliver Dibben, Cassandra Jibara, Leslie Arney, Laura Kinser, Yuyang Tang, Marcia Hobbs, Irving Hoffman, Peter Kazembe, Corbin D. Jones, Persephone Borrow, Susan Fiscus and Myron S. Cohen. Volunteers participating in this study were attending the Kamuzu Central Hospital and the UNC Project in Lilongwe, Malawi.

AIDS Virus Lineage Much Older than Previously Thought. 16/9/10

An ancestor of HIV that infects monkeys is thousands of years older than previously thought

An ancestor of HIV that infects monkeys is thousands of years older than previously thought, suggesting that HIV, which causes AIDS, is not likely to stop killing humans anytime soon, finds a study by University of Arizona and Tulane University researchers.

The simian immunodeficiency virus, or SIV, is at least 32,000 to 75,000 years old, and likely much older, according to a genetic analysis of unique SIV strains found in monkeys on Bioko Island, a former peninsula that separated from mainland Africa after the Ice Age more than 10,000 years ago. The research, which appears in the Sept. 17 issue of the journal Science, calls into question previous DNA sequencing data that estimated the virus' age at only a few hundred years.

The study results have implications for HIV. SIV, unlike HIV, does not cause AIDS in most of its primate hosts. If it took thousands of years for SIV to evolve into a primarily non-lethal state, it would likely take a very long time for HIV to naturally follow the same trajectory.

"HIV is the odd man out because, by and large, all the other species of immunodeficiency viruses impose a much lower mortality on their host species," said Michael Worobey, a professor in the UA's department of ecology and evolutionary biology, who led the study in conjunction with virologist Preston Marx of Tulane University.

"So, if SIV entered the picture relatively recently as was previously thought, we would think it achieved a much lower virulence over a short timescale," Worobey said. "But our findings suggest the opposite. If HIV is going to evolve to lower virulence, it is unlikely to happen anytime soon."

The study also raises a question about the origin of HIV, which scientists believe evolved from SIV. If humans have been exposed to SIV-infected monkeys for thousands of years, why did the HIV epidemic only begin in the 20th century?

"Something happened in the 20th century to change this relatively benign monkey virus into something that was much more potent and could start the epidemic. We don't know what that flashpoint was, but there had to be one," Marx said.

Finding these virus strains trapped on Bioko Island settles a long-standing debate, Worobey said.

"It's like finding a fossilized piece of virus evolution," he said. "We now have this little island that is revealing clues about SIV, and it says, 'It's old.' Now we know that humans were almost certainly exposed to SIV for a long time, probably hundreds of thousands of years."

"Reconstructing the evolutionary past by comparing the genes of these viruses is like looking out onto the ocean," Worobey said. "You can see a long way, but you don't know what lies beyond the horizon. At some point in the past, you don't know what happened. There is a whole lot of ocean out there that you can't get at with the methods that we have been using in trying to tease apart the relationships among these pathogens."

According to Worobey, SIV was distributed across the African continent before Bioko Island separated from the continent about 10,000 years ago.

"When that happened, whatever viruses were circulating at the time became isolated from the virus populations on mainland Africa," he said.

Marx, a virologist at the Tulane National Primate Research Center, tested his theory that SIV had ancient origins by seeking out DNA samples from monkey populations that had been isolated for thousands of years.

His research team collected bush meat samples from Bioko Drills (Mandrillus leucophaeus). The scientists found four different strains of SIV that were highly genetically divergent from those found on the mainland. Worobey then compared DNA sequences of the viruses with the assumption that the island strains evolved in isolation for more than 10,000 years.

The computer modeling showed the rate of mutation to be much slower than previously thought, indicating that the virus is between 32,000 and 75,000 years old. These dates set a new minimum age for SIV, although it is likely to be even older, Marx said.

Worobey said the study has implications for a lot of rapidly evolving pathogens.

"Our methods are great to describe and predict the short-term changes of viruses like the flu or HIV, but we need to be skeptical of inferences in deep time. We found there is a big disconnect between the rapid evolution for which those pathogens are famous and the incredible degree of conservation we've found."

"Being able to study these viruses in an isolated setting is a unique opportunity," he added.

"As far as we know, there is no other place like Bioko Island," Worobey said. "Nowhere else could we do this kind of deep time calibration. Some of the primate species on Bioko only have a few hundred individuals left and might go extinct in the not-too-distant future. We might not have been able to do this research 10 or 20 years from now."

"Looking into the eyes of these animals and knowing they carry the progenitor of HIV in their bodies sends a shiver down my spine."

Funding for Worobey's participation in this research was provided by a grant from the David and Lucile Packard Foundation.

Antibodies for AIDS found. 8/7/10

The virus is difficult to fight in part because it attacks immune system cells and in part because it mutates constantly

Washington - Researchers have discovered antibodies that can protect against a wide range of AIDS viruses and said they may be able to use them to design a vaccine against the fatal and incurable virus.

The bodies of some people make these immune system proteins after they are infected with the AIDS virus, when it is too late for them to do much good. But a properly designed vaccine might help the body make them much sooner, the researchers reported in Friday's issue of the journal Science.

"I am more optimistic about an AIDS vaccine at this point in time than I have been probably in the last 10 years," Dr Gary Nabel of the National Institute of Allergy and Infectious Diseases, who led the study, said in a telephone interview. Two of the antibodies can attach to and neutralize 90% of the various mutations of the human immunodeficiency virus that causes Aids, Nabel said.

"This is an antibody that evolved after the fact. That is part of the problem we have in dealing with HIV - once a person becomes infected, the virus always gets ahead of the immune system," Nabel said.

"What we are trying to do with a vaccine is get ahead of the virus."

AIDS infects about 33 million people globally, according to the United Nations AIDS agency Unaids. It has killed 25 million people since the pandemic began in the early 1980s and there is no vaccine or cure, although drugs can help control it.

The virus is difficult to fight in part because it attacks immune system cells and in part because it mutates constantly, making it a moving target for drugs or the immune system.

It has been almost impossible to make a vaccine that will affect the virus. Last September, researchers reported their biggest success yet with a vaccine that appeared to slow the rate of infection by about 30% in Thai volunteers but the trial raised many questions.

Moving targets

Researchers have been looking for parts of the virus that do not mutate so they can design vaccines that will protect against these constantly changing versions.

Nabel's team found two of the antibodies in the blood of a patient infected with HIV who had not become ill despite the infection. Such people are called non-progressors and researchers study their immune systems to find out why they control the virus better than most patients.

They then found the immune system cells called B-cells that made these particular antibodies, using a new molecular device that they invented.

In yet another experiment, they managed to freeze one of the antibodies in the process of attaching to and neutralising the virus, getting an atomic-level image in a process called x-ray crystallography.

Being able to "see" what the structure looks like could enable researchers to design a vaccine using a process called rational vaccine design, akin to an established technique for making drugs called rational drug design, Nabel said.

It may also be possible to design gene therapy to help patients make these antibodies themselves, or use an older technique that transfuses the antibodies directly.

One of the antibodies, called VRC01, partially mimics the way an immune cell called a CD4 T-cell attaches to a piece of the Aids virus called gp120, the researchers said.

"The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralize such an extraordinary range of HIV strains," Dr John Mascola, who worked on the study, said in a statement.

"The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use," NIAID director Dr Anthony Fauci added in a statement.

"In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases."

Biologists Develop Machine to Remove Viruses from Blood. 1/6/10

It works much like a dialysis machine, using thin fibers to capture and remove viruses from the blood it filters

Infectious disease experts designed a machine called the hemopurifier. It works much like a dialysis machine, using thin fibers to capture and remove viruses from the blood it filters. The machine requires the drawing of blood through an artery, which is sent through a tube into the machine, then back into the body. It can treat a number of illnesses.

Every day, 14,000 people are infected with HIV, the virus that leads to AIDs. There's no cure, but now a breakthrough -- a machine that could clean blood, keeping more and more people alive longer.

"I remember lying in bed thinking, 'I am going to die. I'm going to die. I feel so sick.' And I remember thinking laying in that bed, 'And I know exactly what it is,'" HIV patient John Paul Womble, told Ivanhoe. HIV could kill Womble. He watched his father die from the virus and now he is living the rest of his life with it. "I've got to live as healthy as I can, but this virus is not going to control me," he says. Now, a machine could help clean Womble's infected blood and keep him healthier, longer.

"It's designed to mimic the natural immune response of clearing viruses and toxins before cells and organs can be infected," Jim Joyce chairman and CEO of Aethlon Medical in San Diego, told Ivanhoe. Developed by infectious disease and biodefense experts, the hemopurifier works like a dialysis machine. Antibodies on these spaghetti-like fibers capture and remove viruses as blood filters through it.

"Your entire circulation flows through the cartridge about once every eight minutes," Joyce explains. The entire process takes less than a few hours. It could help patients infected with HIV, hepatitis C, as well as people with the measles, mumps and the flu. "The cartridge is able to selectively capture viruses."

A larger version of the machine would be used in a hospital, but a smaller one could be taken to emergencies. It could be a life-safer against the avian flu or bio-weapons like Ebola and small pox, giving people a chance to survive a deadly attack, whether it's from a terrorist or a virus.

"I don't have to be afraid," Womble says. "I have a virus. I've got to do something about that virus. I've got to treat that virus. I've got to live as healthy as I can." The hemopurifier is also a leading treatment candidate to protect United States civilian and military populations from bioterror threats and emerging pandemic threats like the bird flu and dengue fever that are untreatable with drugs and vaccines.

REMOVING VIRUSES FROM BLOOD: The hemopurifier uses antibodies to remove viruses as blood filters through it. It is designed to filter out viruses and toxins before they attack organs. The method is very similar to dialysis, and can be used to help patients with HIV, Hepatitis C, the measles, mumps, the flu, and more. It can also begin working before doctors identify the cause of the illness.

WHAT IS DIALYSIS? Hemodialysis is often used as a treatment for end stage renal disease (ESRD), or kidney failure, in which blood is removed from the body, filtered through an artificial kidney and then the cleaned blood is returned to the body. In the US, hemodialysis is the most common treatment for people who have kidney failure. However, dialysis is also a painful, expensive procedure, and while it cleans the blood well enough to maintain existence, it does little to improve a patient's overall quality of life. Also, data shows that if patients get a transplant before they get to the point of dialysis, they do better in the longer term.

Blood can be 'Cleaned' of HIV. 7/6/10

People infected with HIV can now donate blood

AllAfrica

Nairobi — People infected with HIV can now donate blood, according to a new study.

The research paper says that, using simple and inexpensive technology, infected blood can be cleaned of the virus and be safely used for transfusion.

The study authors say this would help close the current blood supply gap in the country.

The findings are among the presentations at the 29th World Congress of Biomedical Laboratory Science being held at the Kenyatta International Conference Centre in Nairobi.

Titled Can HIV Positive Individuals be Safe Blood Donors? the paper by Dr Samwel Oketch from the New Nyanza Provincial General Hospital shows that washing red cells makes them free of HIV plasma RNA, making it safe for transfusion.

The conference, which ends on Thursday, is being held in the continent for the first time and brings together about 600 laboratory technicians and medical professionals from more than 40 countries.

The country is facing a crisis as fewer people turn up to voluntarily give blood except in instances where they are needed to save the life of relatives or friends.

The shortage of blood stocks stems from the fear that blood donors are tested and informed of their HIV status.

Statistics from the National Blood Transfusion Service show that the prevalence of HIV among blood donors is currently at 1.3 per cent, down from 6.4 per cent in 1994.

Students are increasingly forming the core group of blood donors and blood banks are reported to experience shortages during school holidays.

If the study results are adopted, HIV positive persons could become possible blood donors.

According to the researchers, by using different HIV testing kits, they were able to clean the blood of any HIV trace using ordinary saline solution. Saline is a sterile solution of table salt and water.

The study was conducted between January and February last year at a regional blood transfusion centre in Kisumu.

Another paper presented at the conference called for confirmatory tests on discarded blood to avoid doing away with supplies that could be free of infections.

Could HIV Be a Matter of Biology? 10/8/10

Africa's HIV epidemic may not be driven by behaviour alone according to a new study

Africa's HIV epidemic may not be driven by behaviour alone according to a new study suggesting that Kenyan women are more biologically susceptible to the virus.

The study compared CD4 cells [white blood cells that lead the immune system's response to infections] from cervical cell samples of young women from Kisumu, Kenya with those of young women from San Francisco, California.

Researchers found that the samples from the Kenyan women had a much higher number of "activated" CD4 cells - normally dormant CD4 cells that have reacted to an infection in the body.

Previous studies have shown that a critical mass of these activated CD4 cells may be crucial in allowing the HIV virus to replicate locally before it can spread throughout the body. This is because HIV spreads by infecting CD4 cells which multiply to fight an infection.

The cervical samples from the Kenyan women also had lower levels of the innate proteins that can protect against HIV infection, and higher levels of CD4 cells with the receptors that allow HIV to attach and replicate.

The authors argue that these findings may suggest that biological differences partly explain why African women have much higher HIV prevalence rates than their American counterparts.

The study by researchers from the University of California, San Francisco, and the Kenya Medical Research Institute, was published in a recent edition of the journal, AIDS.

Environmental impact

[If] we found out that other infections increased people's risk of HIV, [then partial prevention] would be a matter of rolling out [basic] public health measures

Understanding the reasons for the differences was beyond the study's scope, but the researchers posit that they may be the result of infections, such as malaria, which are endemic to parts of Africa and cause activated CD4 cells to spike in parts of the body, including the reproductive tract.

Lead researcher Dr Craig Cohen cautioned against generalizing the results of the study to regions outside East Africa, but said if larger studies proved the theory about the role of endemic disease in HIV infection to be correct, it could revolutionize prevention efforts.

"Let's say we found out that other infections, [like intestinal worms], increased people's risk of HIV," he told IRIN/PlusNews. "If that was the case, it would be a matter of rolling out public health measures [in sub-Saharan Africa] that were put in place in countries like the United States a hundred years ago."

Cohen said the findings did not minimize the need to address known HIV risk factors, including multiple concurrent partners, transactional sex and gender inequality, which prevented women from negotiating safer sex.

Cohen and his team have submitted a funding proposal to the US National Institute of Health to conduct a larger follow-up study to determine the effect of endemic infections, such as intestinal parasites and malaria, on activated CD4 cells in the cervix, and their relationship to HIV susceptibility. If their hypothesis about the role of biology in HIV infection is confirmed by larger studies, it could help de-stigmatise HIV.

"I think many people around the world, people who probably affect funding, think of HIV as a problem among 'poor people in Africa', but that it's really 'their fault'," Cohen told IRIN/PlusNews. "I hope that this study gets away from that in saying that part of HIV infection may be the conditions in which people live."

Despite Countless Changes, Original HIV Infection Lurks Within. 29/6/10

Original version that caused the infection is still present in the body months later.

Scientists have been surprised to learn that, despite thousands of changes that viruses like HIV undergo in rapid fashion to evade the body's immune system, the original version that caused the infection is still present in the body months later.

The finding, published in the June issue of the Journal of Virology, is the result of an uncommonly detailed look at the cat-and-mouse action that takes place in an organism shortly after infection. The work is aimed at understanding the earliest stages of infection by HIV more thoroughly, to help scientists develop ways either to quash the infection outright or to develop a vaccine to prevent infection.

The research, which was conducted by scientists at the University of Rochester Medical Center, is based on an analysis of more than 100,000 genetic snippets of a virus known as SIV, or simian immunodeficiency virus, which infects monkeys and is a close cousin of HIV.

While HIV has flummoxed scientists for nearly three decades, that's certainly not because our immune system fails to respond. Rather, within two or three weeks of infection, the onslaught of immune cells puts the virus on the run to such an extent that the virus must mutate rapidly to evade the body's defenses.

HIV changes quickly and continually, creating thousands and thousands of mutated versions of itself in a process called "viral escape." The virus changes; the immune cells hunting it down change in response; and the virus changes again, and so on, in a kind of molecular arms race.

"Viral escape is a significant phenomenon in HIV -- it's what allows HIV to elude the immune system," said Ha Youn Lee, Ph.D., the assistant professor in the Department of Biostatistics and Computational Biology who led the project.

"The dynamics in the earliest stage of infection by HIV are incredibly complex, and understanding what happens is crucial for developing a vaccine," Lee added.

To do the study, Lee's team applied a mathematical model to data originally gathered by David O'Connor, Ph.D., at the University of Wisconsin at Madison, who studies how SIV evolves. Lee's team analyzed the genetic features of three key sections of the SIV genome as they changed during the first few months of infection in eight macaque monkeys, part of an effort to quantify how quickly the process of viral escape occurs.

The research took advantage of a method known as ultradeep sequencing, which provides hundreds or thousands of glimpses of a single genetic change, compared to approximately 50 or so looks using conventional methods.

"This new technology is very exciting," said Lee. "It allows us to look at the earliest stages of infection in more depth than we could otherwise, and to quantify exactly what is going on in the body. If we can understand it more completely, we can fine-tune vaccines under development."

As expected, the team found that immune cells known as CD8+ T-lymphocytes, also known as cytotoxic T cells, are a powerful force in the life of SIV when it first causes infection. While scientists have known that the CD8 attack on the virus is strong, the latest work quantifies the body's response. They found that the original portions of the virus degrade 400 times faster in response to CD8 cells than they would have if those cells weren't a factor -- what scientists call significant "selective pressure" on the virus.

The team also found that SIV creates such mutants in response to the assault by CD8 cells at about the same rate as HIV does.

But the most striking finding is that the original viral genetic sequences are still present in the body months after the initial infection, at a time that scientists call the "viral set point," which occurs about two to five months after infection. It's a signal of just how difficult it is for the body to eradicate HIV from the body -- key portions of the virus have managed to survive despite the immense immune assault.

"It's a surprise that the original virus stays in the body so long," said Stephen Dewhurst, Ph.D., professor of Microbiology and Immunology and one of the study authors.

"We know that the virus confronts such a strong response from the body's immune system that the virus evolves quickly to cope with it. Yet, the virus is able to establish a reservoir somewhere in the body, where it continues to reproduce and does not have to respond to the threat from the immune system," Dewhurst added.

In addition to Lee and Dewhurst, other authors of the paper are first author Tanzy Love, Ph.D., assistant professor of Biostatistics; Sally Thurston, Ph.D., associate professor of Biostatistics; and Michael Keefer, M.D., professor of Medicine.

The work was funded by the National Institute of Allergy and Infectious Diseases and supported by the University's Developmental Center for AIDS Research

Did the End of Smallpox Vaccination Cause the Explosive Spread of HIV? 18/5/10

Vaccinia immunization, as given to prevent the spread of smallpox, produces a five-fold reduction in HIV replication in the laboratory

Vaccinia immunization, as given to prevent the spread of smallpox, produces a five-fold reduction in HIV replication in the laboratory. Researchers writing in the open access journal BMC Immunology suggest that the end of smallpox vaccination in the mid-20th century may have caused a loss of protection that contributed to the rapid contemporary spread of HIV.

Raymond Weinstein, a family doctor turned laboratory scientist at George Mason University, Manassas, Virginia, worked with a team of researchers from George Washington University and UCLA. The researchers looked at the ability of white blood cells taken from people recently immunized with vaccinia to support HIV replication compared to unvaccinated controls. They found significantly lower viral replication in blood cells from vaccinated individuals.

Weinstein said, "There have been several proposed explanations for the rapid spread of HIV in Africa, including wars, the reuse of unsterilized needles and the contamination of early batches of polio vaccine. However, all of these have been either disproved or do not sufficiently explain the behavior of the HIV pandemic. Our finding that prior immunization with vaccinia virus may provide an individual with some degree of protection to subsequent HIV infection suggests that the withdrawal of such vaccination may be a partial explanation."

Smallpox immunization was gradually withdrawn from the 1950s to the 1970s following the worldwide eradication of the disease, and HIV has been spreading exponentially since approximately the same time period. Weinstein and his colleagues propose that vaccination may confer protection against HIV by producing long term alterations in the immune system, possibly including the expression of a certain receptor, CCR5, on the surface of a person's white blood cells which is exploited by both viruses.

Speaking about the results, Weinstein said, "While these results are very interesting and hopefully may lead to a new weapon against the HIV pandemic, they are very preliminary and it is far too soon to recommend the general use of vaccinia immunization for fighting HIV."

Drug-Resistant HIV Strain Noted. 24/8/11

Four cases of an HIV strain resistant to first line treatment have been reported at Father O'hea Hospital in Zvimba Zimbabwe

AllAfrica

Four cases of an HIV strain resistant to first line treatment have been reported at Father O'hea Hospital in Zvimba and were confirmed by tests conducted in Uganda recently.

The same tests were also conducted on blood samples collected from people initiated on anti-retroviral drugs at Parirenyatwa, Harare and Mpilo Hospitals.

The revelation was made by a laboratory scientist at the hospital, Mr Christopher Solopa recently during a week-long workshop for journalists in Mashonaland West province organised by the National Aids Council.

"The tests were conducted to establish the efficacy of the drugs on our patients and find if there are cases of resistance.

"The results we have got so far shown that there are four cases of resistance at Father O'hea," he said.

The samples, he said, had to be sent to Uganda as the country does not have the requisite equipment as it is expensive to set up. Mr Solopa said strides have been, however, made to equip the country's laboratories with World Health Organisation-certified equipment so that the tests can be conducted in the country.

Currently, South Africa and Uganda have the equipment in Africa. Results for the three other hospitals could not be established by the time of going to print.

Resistance has been attributed to failure by people to adhere to treatment or absconding from taking the drugs. Father O'hea Hospital opportunistic infection outreach nurse, Ms Chengetai Lunga, said the outreach programme had managed to reduce cases of people defaulting from collecting and using their drugs. 3 000 patients are getting ARVs every month.

Experts Caution on HIV/AIDS Cure Excitement. 18/7/10

There is a need to check and make sure of some facts first.

The Citizen

It could be too early for the public to start celebrating the news that a cure for the deadly HIV virus that causes Aids has finally been found, medical experts have warned.

It was reported last week that US-based scientists may have finally hit the home stretch in the long search for a cure for the disease that has ravaged nations, killing millions of people annually.

The US researchers said they have discovered a protein that can protect against a wide range of HIV, and that they now can design a vaccine against the incurable virus

Dr Garry Nabel of National Institute of Allergy and Infectious Diseases, who led the US study, said the discovered proteins, called antibodies, are used by the bodies defence system to identify and neutralise foreign objects, such as bacteria and viruses.

“I am more optimistic about an Aids vaccine at this point than I have been probably in the last 10 years,’ Dr Nabel was quoted as saying, sparking unprecedented world-wide coverage of the discovery.

Welcoming the development, local medical experts and stakeholder in the HIV/Aids campaigns have termed it a positive development towards finding a cure for the scourge.  

But Professor Fred Mhalu of the Muhimbili University of Health and Allied Sciences warned that it is too early for Tanzanians to celebrate, thinking that a cure for HIV/Aids has been found.

Professor Mhalu said there have been similar reports in the past, which are yet to fully yield anticipated and positive results.

“It is a stepping stone towards finding a final treatment, but I can’t say for sure it is already a solution, although prospects are truly high at such level,” he told the Sunday Citizen.

Professor Mhalu heads the university’s department of Microbiology and Immunology, which has also been involved in similar research for trials for a HIV/Aids cure using volunteers from the army. He said their research has gone through two stages with satisfying results.

Asked how long it could take for the US colleagues to confirm their case, Prof Mhalu said: “That is merely a protein antibody, let’s wait until a vaccine that can stimulate it is attained, you can’t say exactly how long.”

He said scientists will receive a clear picture during the forthcoming Aids vaccine conference scheduled for Atlanta, Georgia from September 28 to October 1.The conference is a major venue for medical researchers, providing a forum, in which highest scientific HIV researches are presented and debated.

Meanwhile, the Tanzania network for religious leaders living with HIV/Aids (Tanerela) has expressed its optimism over the latest development.

“I have been following the debate and I am of the view that this time round we might have a cure,” said reverend Amin Sandewa, a former Luthran church living with HIV/Aids.

The impact of this, he said, is that they will have more people voluntary testing for their HIV status. “Many people now fear to test, but once we have the cure, I think, more people will come out and test,” he said.

For his part, the minister for Health and Social Welfare, Professor David Mwakyusa, said there is a need to check and make sure of some facts first.

Speaking over the telephone from Dodoma, Prof Mwakyusa said: “Usually we are guided by scientific journals, and the World Health Organisation. But now I would say what I have seen indicates preliminary reports.”

He added: “It is only when we go through them and convinced it is suitable for our country, we’ll be able to say much. There are things like costs and suitability of the cure to Tanzania.”

Efforts in the past to find a vaccine that could defeat the mutations of the virus have been almost impossible. Last September, researchers reported the biggest success yet with a vaccine that appeared to slow down the rate of infection by about 30 per cent among Thai volunteers.

But the trial left many questions unanswered.  Scientists have been looking for parts of the virus that do not mutate, so they can design a vaccine that will protect against the constantly changing versions.

Gene Therapy Shows Promise for Blocking HIV, Controlling AIDS. 16/6/10

The results may help researchers hunting for ways to cure HIV patients or block the AIDS virus without putting people on toxic medicine for the rest of their lives.

Bloomberg Businessweek

Bloomberg -- Two cutting-edge medical technologies, stem cell transplantation and gene therapy, were combined in an attack on the AIDS virus that may lead to new strategies for treating people infected with HIV.

Researchers at the City of Hope, a nonprofit research institute near Los Angeles, extracted stem cells from the blood of four people with AIDS-related lymphoma, a blood cancer, and modified some of them to carry anti-HIV genes. The altered cells were returned to the patients’ blood without harming them and remained there for two years, a sign that if given in greater number, they might be able to suppress the AIDS virus.

The results may help researchers hunting for ways to cure HIV patients or block the AIDS virus without putting people on toxic medicine for the rest of their lives. Potent antiviral drugs suppress the virus and allow those infected to live near- normal lives. Yet the medicines are unaffordable to millions in poor countries and cause side effects that may shorten the lives of people who use them.

“One of the problems with antiviral therapy is that it has almost led to the perception that HIV is cured and that’s not true,” said David Schaffer, a professor of bioengineering at the University of California, Berkeley, who co-directs the school’s stem cell center. “If you could develop a therapy to make HIV-proof blood cells, then you could create a true cure for HIV. This is a very promising clinical trial that takes us in that direction.”

Schaffer, who was not involved in the research, wrote a commentary accompanying the study. Both were published today in the journal Science Translational Medicine.

Current Treatments

More than 34 million people worldwide are infected with HIV, the virus that causes AIDS, and about 2 million lost their lives to AIDS in 2008, according to the World Health Organization, based in Geneva. Efforts to develop vaccines to prevent high- risk people from becoming infected have so far failed, leaving the drug cocktails made by companies led by Gilead Sciences Inc., based in Foster City, California, and London-based GlaxoSmithKline Plc as the method of treating people with HIV.

The City of Hope research builds on an experiment reported last year by a German doctor, Gero Hutter, in the only known case of an AIDS patient being cured. The patient, who had AIDS and leukemia, was given a stem-cell transplant from a donor whose rare gene variant caused his immune cells to lack a receptor called CCR5. Without this receptor, HIV can’t infect immune cells.

New Blood

Hutter’s patient had his blood-forming stem cells wiped out and replaced by those of the donor. The transplant rebuilt his blood system and cured his leukemia. His immune cells also became resistant to HIV, allowing him to stop the antiviral drugs he’d been taking for 10 years.

Three years after the transplant, the patient still has no detectable HIV, Hutter said in a June 5 interview.

The City of Hope researchers extracted patients’ blood- forming stem cells, genetically modified some of them and infused them back into the patients after first wiping out their bone marrow and blood system.

The modified cells were altered using a harmless virus to carry three different gene sequences into them. This triple- therapy approach was modeled on drug cocktails that attack HIV in multiple ways to overcome drug resistance, study leader John Rossi said in a June 14 telephone interview.

One of the molecules cuts the CCR5 sequence in an effort to bar the door to a cell and keep HIV from entering, the second squires away a protein that the virus uses to replicate and the third knocks out a key piece of genetic machinery that HIV needs to maintain itself, Rossi said.

Multiple Attacks

“The idea is to hit multiple sites of the virus with different types of gene therapy so resistance to one doesn’t make it resist others,” Rossi said. “The three work better than any two together.”

The transplant procedure is risky and was only attempted on HIV patients who needed it to treat their cancer. All four patients remain free of their lymphoma about two years after the treatment, Rossi said.

The number of gene-modified cells returned to the patients in the study was too small to cure or even improve their HIV infections, Rossi said. The next step is to replace a much larger portion of a patient’s stem cells with gene-modified cells and see if they can substantially reduce their HIV level.

Rossi and his colleagues also are exploring ways to alter the transplant procedure to make it less toxic. That may allow the procedure to be used on HIV patients who don’t have cancer.

The research was funded in part by Benitec Ltd., a Melbourne, Australia-based biotechnology company that developed one of the gene therapy treatments used in the trial.

--Editors: Donna Alvarado, Andrew Pollack

HIV Can Hide, Say Researchers. 08/03/10

Washington - The virus that causes Aids can hide in the bone marrow, avoiding drugs and later awakening to cause illness, according to new research that could point the way toward better treatments for the disease.

News24

Finding that hide-out is a first step, but years of research lie ahead.

Dr Kathleen Collins of the University of Michigan and her colleagues report in this week's edition of the journal Nature Medicine that HIV can infect long-lived bone marrow cells that eventually convert into blood cells.

The virus is dormant in the bone marrow cells, she said, but when those progenitor cells develop into blood cells, it can be reactivated and cause renewed infection. The virus kills the new blood cells and then moves on to infect other cells, said.

"If we're ever going to be able to find a way to get rid of the cells, the first step is to understand" where a latent infection can continue, Collins said.

Hide-out

In recent years, drugs have reduced Aids deaths sharply, but patients need to keep taking the medicines for life or the infection comes back, she said. That's an indication that while the drugs battle the active virus, some of the disease remains hidden away to flare up once the therapy is stopped.

One hide-out was found earlier in blood cells called macrophages. Another pool was discovered in memory T-cells, and research began on attacking those.

But those couldn't account for all the HIV still circulating, Collins said, showing there were more locations to check out and leading her to study the blood cell progenitors.

Finding these sources of infection is important because eliminating them would allow Aids patients to stop taking drugs after their infection was over. That's critical in countries where the treatment is hard to afford and deliver.

"I don't know how many people realise that although the drugs have reduced mortality we still have a long way to go," Collins said in a telephone interview. "That is mainly because we can't stop the drugs, people have to take it for a lifetime."

The research was funded by the National Institutes of Health, Burroughs Wellcome Foundation, University of Michigan, Rackham Predoctoral Fellowship, National Science Foundation and a Bernard Maas Fellowship.

- SAPA

HIV Findings Offer Hope for 'Cure'. 18/8/10

This caused the infected cells to go into "panic mode" and self-destruct.

Israeli researchers said they have discovered a way of killing off cells infected with HIV that offered hope for a cure for the disease.

The technique involved getting the virus to overload the host cell with viral DNA, which made the cell self-destruct and kill off the virus.

However they warned that so far they have only "cured" HIV in small dishes of cells in a laboratory. Their findings would be  published in the journal Aids Research and Therapy.

Antiretroviral therapy, the medical world's strongest existing weapon against the virus, stopped HIV from replicating, but did not eradicate it from host cells or eliminate those cells. The researchers said that their approach could lead to an anti-HIV therapy that would eradicate the virus.

The study

One of the authors of the paper, Professor Abraham Loyter of Jerusalem's Hebrew University, said HIV spread through the human body when its DNA was incorporated into the genome of host cells.

However the virus inserted only enough DNA to replicate, and not enough to make the host genome unstable, which would lead to the death of the infected cells in a process called apoptosis.

Loyter said he and his team used amino acids called peptides to boost the integration of HIV DNA into the human genome. This caused the infected cells to go into "panic mode" and self-destruct.

The experiment did not have any effect on non-infected cells.

"Whilst this research is promising, a major caveat with these studies is that they are preliminary," Loyter said. "So far these experiments have only been shown to 'cure' HIV from small dishes of cultured cells in the authors' laboratory, but the findings are an exciting development in the quest to eradicate this devastating global pandemic."

The process "may eventually be developed into a new and general anti-viral therapy", he said. - (Sapa, August 2010)

HIV May Hide in the Brain. 31/8/10

The brain can be a convenient hiding place for HIV, the virus that causes AIDS.

That's the finding of Swedish researchers who analysed samples from about 70 HIV-infected patients who'd been taking anti-HIV drugs. The tests showed that about 10% of the patients, a larger proportion than expected, had traces of HIV in their spinal fluid but not in their blood.

Another study by the researchers found that 60% of 15 HIV-infected patients treated with medication for several years showed signs of inflammation in their spinal fluid, although the levels were lower than they were without treatment.

Anti-HIV drugs can prevent the virus from multiplying, but the virus also infects the brain and can cause damage if the infection isn't treated, according to lead researcher Dr Arvid Eden, a doctor and researcher at the Institute of Biomedicine at the Sahlgrenska Academy at the University of Gothenburg.

The findings

"Antiviral treatment in the brain is complicated by a number of factors, partly because it is surrounded by a protective barrier that affects how well medicines get in," Eden said. "This means that the brain can act as a reservoir where treatment of the virus may be less effective."

It is unclear whether small quantities of the virus in spinal fluid represent a risk for future complications, researchers said. Still, the findings indicate that "we need to take into account the effects in the brain when developing new drugs and treatment strategies for HIV infection," Eden added. (August 2010)

HIV is a 20th-Century Disease that Needs 21st-Century Research. 10/8/10

We need smarter approaches to clinical trials that test more concepts in less time, for less money, while preserving safety, community engagement and ethical guidelines

The Global and Mail

The fight against HIV-AIDS turned an important corner with the recent announcement of new data from South Africa that a vaginal gel significantly reduced HIV infections in women. The gel, known as a microbicide, contains a drug that reduced infections by 39 per cent among all women in the study, and by more than half in women who used it regularly. This major step forward in AIDS prevention research comes less than a year after a vaccine regimen tested in Thailand reduced infection risk by 31 per cent.

Neither experimental product is good enough to use today. The microbicide requires at least one more large-scale clinical trial. The vaccine’s modest, short-term protection must be improved on with better approaches. But both studies, along with other research advances being reported with increasing frequency, provide clear evidence we have entered a highly promising era in HIV-prevention research. Microbicides, vaccines and other new approaches will one day join proven HIV-prevention strategies, including condoms, male circumcision and clean needles. How soon that day comes will depend on whether funders and the scientific community can develop the more collaborative approaches to HIV prevention research needed to address this fast-moving epidemic.

For years, global attention has focused on enhancing access to AIDS treatment. Thanks to programs such as the U.S. PEPFAR initiative, the Global Fund to Fight HIV, TB and Malaria, United Nations programs and foundation efforts led by Bill Clinton and a handful of others, the number of people receiving life-saving HIV treatment has grown from 400,000 at the start of the decade to five million people. As a result, AIDS-related mortality has dropped 18 per cent in sub-Saharan Africa.

Despite Herculean efforts to expand access to treatment, however, only a third of those who need HIV drugs receive them – a proportion sure to drop as millions more are infected each year. While access to treatment deserves increased support, treatment alone will not end this pandemic. Smarter, more nimble, better-funded research is needed to build on recent successes and develop practical tools that can slow and one day end this epidemic.

How do we do that? With new approaches to bring funders and scientists from around the world working together to advance HIV prevention and other major public-health goals. The Global HIV Vaccine Enterprise is a unique approach that brings together major funding and policy organizations committed to accelerating the development of an HIV vaccine. HIV vaccine and microbicide research is supported by only a handful of funders, with the U.S. government and the Bill and Melinda Gates Foundation at the head of the list. Many countries with the scientific, financial and social resources necessary to invest in prevention research are still not doing so.

Canadian science has a particular contribution to make. The recent announcement by Health Minister Leona Aglukkaq of the renewed alliance between the government and the Gates Foundation to support HIV vaccine research is welcome news. This will challenge other G20 countries, which need to contribute more to this global effort.

As it becomes clearer that vaccines, microbicides or other drug-based approaches may hold the key to HIV prevention, the pharmaceutical industry can no longer watch from the sidelines. HIV-prevention research requires systematic, strategic approaches that maximize the scientific value of public-private partnerships, minimize risk for industry and permit the sharing of research findings and data.

HIV-prevention trials typically take three to seven years to plan, fund, conduct and analyze. With nearly three million people newly infected each year, we need smarter approaches to clinical trials that test more concepts in less time and for less money, while preserving safety, community engagement and ethical guidelines. This requires a new spirit of global collaboration among funders, researchers, communities, local and national governments, and trial volunteers, as well as a new generation of HIV researchers, encouraged to enter this field by the conviction they can help end this epidemic.

HIV is too great a challenge, and the results of these trials too promising, to continue with hesitant approaches to prevention research. This epidemic is a holdover from the 20th century. It is time for 21st-century research approaches that will speed the effort to end it.

Alan Bernstein is executive director of the Global HIV Vaccine Enterprise and former president of the Canadian Institutes of Health Research. Peter Piot is chair of the Global HIV Vaccine Enterprise, director of the Institute of Global Health at Imperial College, London, and former executive director of the Joint United Nations Program on HIV-AIDS (UNAIDS).

HIV/AIDS Research Breakthrough. 31/01/2010

London - Scientists say they have solved a crucial puzzle about the Aids virus after 20 years of research and that their findings could lead to better treatments for HIV.

British and US researchers said they had grown a crystal that enabled them to see the structure of an enzyme called integrase, which is found in retroviruses like HIV and is a target for some of the newest HIV medicines.

"Despite initially painstakingly slow progress and very many failed attempts, we did not give up and our effort was finally rewarded," said Peter Cherepanov of Imperial College London, who conducted the research with scientists from Harvard University.

The Imperial and Harvard scientists said that having the integrase structure means researchers can begin fully to understand how integrase inhibitor drugs work, how they might be improved, and how to stop HIV developing resistance to them.

When the human immunodeficiency virus (HIV) infects someone, it uses the integrase enzyme to paste a copy of its genetic information into their DNA, Cherepanov explained in the study published in the Nature journal on Sunday.

Some new drugs for HIV - like Isentress from Merck & Co and elvitegravir, an experimental drug from Gilead Sciences - work by blocking integrase, but scientists are not clear exactly how they work or how to improve them.

The only way to find out was to obtain high-quality crystals - a project that had defeated scientists for many years.

"When we started out, we knew that the project was very difficult, and that many tricks had already been tried and given up by others long ago," said Cherepanov.

Grew a crystal

"Therefore, we went back to square one and started by looking for a better model of HIV integrase which could be more amenable for crystallisation."

The researchers grew a crystal using a version of integrase borrowed from another retrovirus very similar to its HIV counterpart.

It took more than 40 000 trials for them to come up with a crystal of sufficiently high quality to allow them to see the three-dimensional structure, they said.

They tested the Merck and Gilead drugs on the crystals, and were able to see for the first time how the medicines bind to, and block, integrase.

Almost 60 million people have been infected with HIV and 25 million people have died of HIV-related causes since the beginning of the Aids epidemic. There is no cure and no vaccine, although drug cocktails can keep patients healthy.

United Nations data for 2008 show that 33.4 million people had HIV and 2 million people died of Aids. The worst-affected region is sub-Saharan Africa, accounting for 67% of all people living with HIV.

- Reuters

How HIV Takes Control of Cell Division: Role of the Vpr Protein in HIV Infection and AIDS. 2/9/10

Vpr blocks normal cell division, a process believed to increase viral replication and to trigger immune cell death

Dr. Éric A. Cohen, Director of the Human Retrovirology research unit at the Institut de recherches cliniques de Montréal (IRCM), and his team published in the online open-access journal PLoS Pathogens the results of their most recent research on the role of the Vpr protein in HIV (human immunodeficiency virus) infection and AIDS (acquired autoimmune deficiency syndrome).

"We previously identified that HIV, when infecting target cells, blocks cell division and induces cell death," says Dr. Cohen. "We then discovered that the Vpr protein was involved in this process."

HIV-1 encodes several proteins, including the viral protein R (Vpr), which plays an important role in the development of acquired immunodeficiency syndrome (AIDS). Vpr blocks normal cell division, a process believed to increase viral replication and to trigger immune cell death. The researchers recently showed that Vpr performs this activity by interacting with a cellular protein complex (E3 ligase) involved in ubiquitination. Ubiquitination is characterized by the conjugation of a small protein called ubiquitin to various other proteins to regulate their degradation or activities. They also demonstrated that Vpr engages this protein complex to ubiquitinate a yet to be discovered host factor, whose degradation triggers the arrest of cell division.

"We understand the process, but we still don't know which cellular factor is targeted by Vpr to block cell division and where these events are occurring within the infected cell," explains Dr. Jean-Phillippe Belzile, a postdoctoral fellow in Dr. Cohen's research unit and first author of the article. "If we can identify this unknown host factor and determine its role in the cell cycle, it will undoubtedly have an impact on our understanding of HIV infection and the processes of immune cell death that characterize AIDS. We believe that the identification of this host factor could, in the long run, lead us to new potential therapeutic targets."

In this study, the researchers demonstrated that Vpr forms mobile structures called foci on the DNA of host cells. They also found that formation of these nuclear foci by Vpr is required to block cell division. They further showed that Vpr engages the E3 ligase within these mobile structures, and uses them to find a DNA-bound cellular protein and target it for degradation. This mechanism, in turn, results in the activation of a host cell response leading to a cell division block.

"Getting such insight into this process is very important, as it gives us and the scientific community a direction to focus our efforts to identify this unknown host factor, thereby contributing to a better understanding of the role of Vpr during HIV infection and AIDS pathogenesis," adds Dr. Cohen.

This research project was supported by the Canadian Institutes of Health Research (CIHR), the Canadian Foundation for Innovation (CFI) and the Canada Research Chairs program. "This is an important step forward in the battle against HIV/AIDS," said Dr. Marc Ouellette, Scientific Director for the CIHR Institute of Infection and Immunity. "Enhancing our knowledge on the molecular mechanism of HIV infection is an excellent example of what fundamental research is all about: finding new approaches and narrowing the focus through discovery that might provide the basis for an effective therapy."

On a global scale, it has been estimated that in 2010, 33 million people lived with HIV, and 2 million deaths were related to AIDS (Source: Joint United Nations Programme on HIV/AIDS (UNAIDS), 2008 Report on the global AIDS epidemic.). According to the Public Health Agency of Canada, approximately 65,000 lived with HIV (including AIDS) in Canada in 2008. They also estimate that the number of new HIV infections ranges from 2,300 to 4,300 per year.

Longer Viral Load is Undetectable, Lower the Risk of Rebound. 20/9/10

Once viral suppression was initially achieved, high levels of adherence were still needed for at least the first year.

AIDSMap

The longer a patient taking HIV treatment maintains an undetectable viral load, the lower their risk of virologic rebound, Canadian investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

“We found that once viral suppression was initially achieved, high levels of adherence were still needed for at least the first year. Over time, however, the risk of viral rebound decreased with maintained viral suppression irrespective of the level of adherence”, comment the investigators.

Nevertheless, the investigators emphasise that patients should aim to take all their doses correctly.

Treatment with combination antiretroviral therapy can extend the life expectancy of HIV-positive patients to near normal levels.

To get the maximum benefit from their treatment, it is necessary for patients to take their treatment correctly. The best outcomes are seen in individuals who take at least 95% of their doses. Adherence below that level has been associated with an increase in viral load and the development of drug-resistant virus.

However, Canadian researchers hypothesised that once initial suppression of HIV was achieved after starting therapy, lower levels of adherence would be needed to needed to maintain an undetectable viral load. This is because the amount of virus capable of reproduction diminishes with longer duration of suppression.

To test their theory, the investigators performed a retrospective study involving 1305 patients starting HIV therapy for the first time between 2000 and 2006. All the patients achieved a viral load below 50 copies/ml. The investigators analysed the factors associated with a subsequent sustained increase in viral load to above 400 copies/ml.

Overall, 274 (21%) of patients experienced virologic rebound. The median time from suppression to below 50 copies/ml and a sustained rebound in viral load was two years.

Factors associated with an increase in viral load were female sex, a history of injecting drug use, starting treatment in 2000-2001, being younger, baseline resistance to antiretroviral drugs, and taking an unboosted protease inhibitor (all p < 0.01).

The duration of prior viral suppression was also important.

Each month of continuous suppression of HIV lowered the risk of rebound by 8%.

At all levels of adherence, the longer HIV was suppressed, the lower the risk of rebound.

For patients with a high level of adherence (95% or better), the probability of rebound was 0.10 when viral load was suppressed for less than twelve months. However, the probability was just 0.04 after viral load had been suppressed for 72 months.

Among individuals with moderate adherence (80% to 94%), the probability of rebound was 0.85 with suppression for up to twelve months and 0.08 at 72 months.

For those with low adherence, the probability of rebound was 0.68 after suppression for twelve months and 0.05 after 72 months.

However, even after taking into account the duration of suppression, patients who took at least 95% of their doses were 11% less likely than with the poorest adherence.

“Our results reinforce the message of to individuals that sustained and near perfect adherence increase the probability of long-term viral suppression, particularly critical at the earliest stages of treatment”, write the authors.

Nevertheless, they conclude that “because the resilience of HAART [highly active antiretroviral therapy] increases over time, it is possible that individuals remain fully suppressed even after missing some doses of medication."

Maraviroc Potentially Useful if Neurological Disease is Present. 15/7/10

Maraviroc (Celsentri) may be a good option for patients with advanced HIV disease and neurocognitive impairment

AIDSMap

Maraviroc (Celsentri) may be a good option for patients with advanced HIV disease and neurocognitive impairment, a small observation study published in the online edition of AIDS suggests.

Six patients took the CCR5 inhibitor as part of combination antiretroviral treatment, and therapeutic concentrations of the drug were detected in the cerebrospinal fluid of four individuals, and HIV viral load fell in this compartment in all patients. “This is consistent with maraviroc contributing to the inhibition of HIV-1 replication in the CNS [central nervous system]”, comment the investigators.

HIV can penetrate the central nervous system, and replication of the virus in brain is associated with the development of serious illnesses such as AIDS-dementia complex.

Not all anti-HIV drugs are able to cross the blood-brain barrier, and some physicians believe that this means that the virus will be able to replicate in the central nervous system, even when a patient is taking otherwise successful antiretroviral therapy.

Most of the HIV isolated from the cerebrospinal fluids uses the CCR5 co-receptor to gain entry to cells, and this is blocked by maraviroc.

Investigators wished to evaluate the efficacy of maraviroc as part of combination antiretroviral therapy in six patients with symptoms of central nervous system disease.

These individuals had a median age of 44, and the median nadir CD4 cell count was 59 cells/mm³.

At the onset of neurological symptoms, two patients were antiretroviral-naïve, their median plasma viral load being 4.8 log₁₀ copies/ml. The remaining four patients were taking HIV treatment, but had a detectable viral load, the median value being 2.4 log₁₀ copies/ml.

All the patients had detectable HIV in their cerebrospinal fluid, median viral load being 3.6 log₁₀ copies/ml.

Tropism testing revealed that five patients had virus with the CCR5 co-receptor, and all six patients added ritonavir-boosted maraviroc to their HIV treatment combination.

After one month of therapy, clinical improvements were observed in five patients. Viral load in all six individuals declined significantly in both plasma (p = 0.03) and cerebrospinal fluid (p = 0.005).

The median plasma concentration of maraviroc was 347 ng/ml. However, although two patients had good concentrations of the drug in their blood, it could not be detected in their cerebrospinal fluid. No correlation was apparent between levels of maraviroc in the blood and concentrations in cerebrospinal fluid.

“We report the effects of maraviroc-containing cART [combination antiretroviral therapy] regimens on CSF viral load in six patients with neurological symptoms. In all cases, both the HIV-1 viral load and cell count in the CSF were significantly reduced within 1 month of treatment”, write the investigators.

However, the investigators note that “all patients were receiving treatment with antiretroviral drugs other than maraviroc, including abacavir, lamivudine, and zidovudine, which are known to cross the BBB [blood brain barrier].”

Nevertheless, the investigators conclude “maraviroc should be considered in cART regimens for advanced stage AIDS patients suffering neurological disease.”

Reference

Melica GM et al. Maraviroc-containing regimen suppresses HIV replication in the cerebrospinal fluid of patients with neurological symptoms. AIDS, online edition, DOI: 10. 1097/QAD.0b013e32833c9353, 2010.

Merck Stops Development of CCR5 Inhibitor Vicriviroc. 15/7/10

Merck has announced that it is to halt all development of the CCR5 inhibitor vicriviroc

AIDSMap

Merck has announced that it is to halt all development of the CCR5 inhibitor vicriviroc, following disappointing data from a phase II study of the drug in people with HIV with no previous history of treatment.

Vicriviroc was acquired by Merck as part of its merger with Schering-Plough, which had been developing the drug for over ten years.

Vicriviroc was designed to block the CCR5 receptor on human CD4 cells, which HIV uses to gain entry into CD4 cells.

Several other companies have attempted to develop drugs of this type, but only one, Pfizer, has managed to successfully bring a CCR5 inhibitor to market. Maraviroc, marketed as Selzentry in the United States and Celsentri in the rest of the world, has so far failed to find a large market. (The drug is now marketed by Viiv Healthcare, Pfizer and Glaxo SmithKline’s co-venture in HIV drug development).

Vicriviroc had had a difficult development pathway, with a concern over a potentially higher rate of malignancies in one phase II study in treatment-experienced patients, and a failure to show added benefit in phase III studies in which the majority of patients were already receiving highly potent background regimens of recently approved new drugs.

Following these results Merck announced that it was abandoning development of vicriviroc as an option for treatment-experienced patients in January 2010.

An earlier study in treatment-naïve patients was abandoned after a number of cases of early viral load rebound led to concerns about the drug’s potency.

The recently halted study in treatment-naïve patients was testing vicriviroc in an innovative nucleoside analogue-sparing regimen, in combination with atazanavir/ritonavir. Merck provided no details of the study outcomes in a letter to investigators announcing the cancellation of the drug development programme, but said the study results would be presented at a future scientific meeting.

Results from a similar study, in which maraviroc was combined with atazanavir/ritonavir, are due to be presented next week at the Eighteenth International AIDS Conference in Vienna.

Nevirapine Toxicity in Women Predicted by Liver Function, Not CD4 Count, Developing Country Study Reports. 1/9/10

Abnormal liver function tests at baseline were predictors for severe liver damage

AIDSMap

Abnormal liver function tests at baseline, not CD4 cell counts over 250 cells/mm³, were predictors for severe liver damage and associated rash researchers among women in Zambia, Thailand and Kenya on a nevirapine-based antiretroviral regimen reported in a multi-country prospective cohort study published in the advance online edition of HIV Medicine.

Close to 70 percent of the estimated 3.5 million people in sub-Saharan Africa and Asia on antiretroviral treatment are on regimens that include nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI).

Nevirapine has proven effective, has no known adverse effects on the unborn child, or long term side-effects. However, it can cause damage to the liver, rash and life- threatening sensitivity, especially in the first few months.

Clinical studies have not given a consistent definition of nevirapine-associated liver damage. Serious liver damage is generally defined in one of three ways, note the authors:

A retrospective analysis undertaken by Boehringer-Ingelheim, nevirapine’s original manufacturer, found that women with a baseline CD4 cell count over 250 cells/mm³   had a greater risk of rash-associated liver damage than those with a baseline under 250. This led the United States Food and Drug Administration (FDA) to issue a warning against women with CD4 cells counts over 250 to take nevirapine unless benefits outweighed the risks. Some studies have supported Boehringer-Ingelheim’s findings while others have not.

Subsequent to the World Health Organization’s recommendations of 2006 and 2009 increasing numbers of women in resource-poor settings have started and will start nevirapine-containing regimens at CD4 cell counts between 250 cells/mm³ and 350 cells/mm³.

The authors note that in spite of the increased numbers of women starting nevirapine-based antiretroviral regimens in resource-poor settings with CD4 cell counts at or above 250 cells/mm³, few studies have looked at the risk of liver damage among this population.

The Non-Nucleoside Reverse Transcriptase Inhibitor Response study, a prospective cohort study in Zambia, Thailand and Kenya was designed to identify risk factors for severe liver damage (grade 3 or 4) and rash-associated liver damage (rash with grade 2 or above liver damage) among HIV-infected women starting nevirapine-based antiretroviral treatment regimens. At enrolment and at weeks 2, 4, 8, 16 and 24 serum alanine transferase (ALT) and aspartate transaminase (AST) were measured and study participants were evaluated for signs and symptoms of hepatitis and rash.  

113 (14%) of the 820 women (497 Zambian, 192 Thai and 131 Kenyan) who started nevirapine-based antiretroviral treatment had abnormal liver function tests (ALT and AST levels) at baseline.

After starting nevirapine-based antiretroviral therapy a total of 41 (5%) women had grade 3 or 4 events (severe liver damage).  Severe liver damage was seen in 12% (13) of the 113 with abnormal liver function tests at baseline compared to 4% of women who had normal liver function tests at baseline (aOR 3.2 95% CI: 1.4-6.8).

Whereas severe liver damage was seen in 5% of those with CD4 cell counts below 250 cells/mm³ as well as in 5% of those with CD4 cell counts above 250 cells/mm³ at baseline (aOR 1.0, 95% CI: 0.-2.5). In a multivariate analysis other baseline variables that included age, body mass index, viral load, concurrent anti-tuberculosis therapy, WHO clinical disease stage and country were not associated with severe liver damage.

The analysis was repeated for each country and the results were the same as noted above.

Similarly rash-associated liver damage was seen in 7 (6%) of the 113 women with abnormal liver function tests at baseline compared to 20 (3%) of 699 women with normal baseline values (aOR 2.8; 95% CI: 1.1-7.1). However, among Thai women rash-associated liver damage appeared more frequently (7%) compared to Zambian (2%) or Kenyan women (2%) (aOR .4; 95% CI: 1.5-7.8). As with severe liver damage other baseline variables, noted above were not linked to rash-associated liver damage.

The analysis was repeated for each country with similar results. While women with a baseline CD4 cell count at or above 250 cells/mm³ were not at increased risk for rash-associated liver damage differing trends were seen in Zambia (OR 0.5; 95% CI: 0.01-3.8) and Thailand (OR 2.3; 95% CI: 0.4-10.3).

The results also showed a decreased risk of rash-associated liver damage among women with baseline CD4 cell counts of 50-199 cells/mm³ compared with those whose CD4 cell counts were below 50 or at and above 200 cells/mm³.

However, the authors caution this should not be seen as evidence to start nevirapine safely in women with CD4 cell counts of 50-199 cells/mm³.  Of the three participants (0.4%) who died with symptoms suggestive of severe liver damage one had a baseline count within this range (68 cells/mm³). All three were receiving anti-tuberculosis therapy. The other two had baseline CD4 cell counts under 50 cells/mm³.

The authors stress that within resource-poor settings health care workers need to pay attention to nevirapine-associated liver damage in women starting antiretroviral therapy regardless of CD4 count and in particular to concurrent use of anti-tuberculosis therapy . WHO recommends efavirenz is substituted for nevirapine because of less interaction with rifampicin.

Monitoring liver function early (at baseline and at 2 and 4 weeks) suggested that the majority of those at risk for liver damage can be identified.

The authors highlighted a possible alternative to reduce the risks of both liver damage and harm to the unborn child: women with baseline CD4 cell counts at or above 250 cells/mm³ can be started on an efavirenz-based regimen for at least six months then changed to nevirapine. The authors suggest that liver damage may not occur because nevirapine is started after the initial rapid immune recovery on antiretroviral treatment has begun.

Limitations according to the authors include:

The authors conclude that among three to five percent of women in three resource-poor settings severe liver damage or rash-associated liver damage was seen in the first 24 weeks after starting a nevirapine-based antiretroviral therapy. Baseline abnormal liver function tests, not CD4 cell counts at or under 250 cells/mm³, predicted both severe liver damage and rash-associated liver damage.  

The authors recommend that in resource-poor settings where liver function (transaminase) testing “is available, testing should focus on early time-points and on women with abnormal baseline ALT or AST results.”

New Class of Anti-HIV Drugs Possible. 4/2/10

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New Insights Into the Mystery of Natural HIV Immunity: Findings May Have Implications for Designing Effective AIDS Vaccine. 6/5/10

A small number of people exposed to the virus progress very slowly to AIDS -- and some never develop the disease at all

When people become infected by HIV, it's usually only a matter of time, barring drug intervention, until they develop full-blown AIDS. However, a small number of people exposed to the virus progress very slowly to AIDS -- and some never develop the disease at all.

In the late 1990s, researchers showed that a very high percentage of those naturally HIV-immune people, who represent about one in 200 infected individuals, carry a gene called HLA B57. Now a team of researchers from the Ragon Institute of Massachusetts General Hospital, MIT and Harvard has revealed a new effect that contributes to this gene's ability to confer immunity.

The research team, led by MIT Professor Arup Chakraborty and Harvard Professor Bruce Walker at MGH, found that the HLA B57 gene causes the body to make more potent killer T cells -- white blood cells that help defend the body from infectious invaders. Patients with the gene have a larger number of T cells that bind strongly to more pieces of HIV protein than people who do not have the gene. This makes the T cells more likely to recognize cells that express HIV proteins, including mutated versions that arise during infection. This effect contributes to superior control of HIV infection (and any other virus that evolves rapidly), but it also makes those people more susceptible to autoimmune diseases, in which T cells attack the body's own cells.

This new knowledge, published online in Nature on May 5, could help researchers develop vaccines that provoke the same response to HIV that individuals with HLA B57 muster on their own, says Walker, who is director of the Ragon Institute and a professor at Harvard Medical School.

"HIV is slowly revealing itself," says Walker. "This is another point in our favor in the fight against the virus, but we have a long way to go."

Most killer T cells are genetically unique and recognize different pieces of foreign proteins, known as epitopes, attached to the surface of cells that have been infected by viruses or bacteria. After a killer T cell grabs hold of such a protein, it becomes activated and starts sweeping the body for more cells that express the same protein, so it can kill them. It also clones itself to produce an army of T cells targeting the invader.

The new Ragon Institute study shows that individuals with the HLA B57 gene produce larger numbers of killer T cells that are cross-reactive, meaning they can attack more than one epitope associated with HIV, including mutants that arise to escape activated killer T cells.

The finding offers hope that researchers could design a vaccine to help draw out cross-reactive T cells in people who don't have the HLA B57 gene. "It's not that they don't have cross-reactive T cells," says Chakraborty. "They do have them, but they're much rarer, and we think they might be coaxed into action with the right vaccine."

The work is a valuable contribution to scientists' understanding of HIV, says David Baltimore, professor of biology and former president of Caltech.

"This is a remarkable paper because it starts from a clinical observation, integrates it with experimental observations, generates a valuable model and derives from the model a deep understanding of the behavior of the human immune system. Rarely does one read a paper that stretches the mind so surprisingly far," says Baltimore, a Nobel laureate in physiology or medicine who now studies HIV and human T cell interactions.

Chakraborty and colleagues had previously developed computational models of T-cell development in the thymus, an organ located behind the breastbone through which T cells must pass in order to become mature killers. There they undergo a selection process designed to weed out cells that might attack the body's own cells (which display pieces of human proteins on their surface). T cells must also demonstrate that they can bind weakly to some human protein fragments. Only a tiny percentage of T cells pass these tests and are allowed to leave the thymus and circulate in the body to defend against viruses, other diseases, and cancerous cells.

Inside the thymus, T cells are exposed to "self-peptides" -- small human protein fragments -- bound to HLA proteins. Chakraborty and co-workers had previously shown that the diversity of self-peptide fragments presented in the thymus influences the kinds of T cells a person can produce. The type and number of self-peptides expressed are determined by the HLA genes, which have hundreds of distinct forms, including HLA B57. Each person carries up to six of them (three inherited from each parent).

Using data from previous studies, the Ragon team found that HLA B57 protein presents fewer types of self-peptides than most other HLA proteins. (HLA B27 is another protein that presents few types of self-peptides and also appears to protect against HIV and promote autoimmune disorders.) In this study, Chakraborty and postdoctoral fellow Elizabeth Read and graduate student Andrej Kosmrlj, lead authors of the paper, used their computer model to study what happens when maturing T cells are exposed to only a small diversity of self-peptides in the thymus.

T cells with receptors that bind strongly to any of the self-peptides in the thymus are forced to undergo cell suicide, because of their potential to attack the body's own cells. Chakraborty and co-workers showed that this means that, for most individuals, most of the body's T cells have receptors that bind to targeted viral proteins via a number of weak interactions, with each interaction making a significant contribution to the binding. Thus, a single mutation to an HIV peptide can potentially evade the immune response.

A different scenario unfolds in people who have the HLA B57 gene. Using their computer model, Chakraborty and colleagues showed that, because those individuals' T cells are exposed to fewer self-peptides in the thymus, T cells with receptors that mediate strong binding to viral proteins via just a few important contacts are more likely to escape the thymus. This makes these T cells more cross-reactive to targeted HIV peptide mutants, because as long as those points in the viral proteins don't mutate, the T cells are still effective. The model also showed that once those T cells are released into the bloodstream, they can effectively attack HIV proteins, even when the virus mutates.

This model also explains why people with the HLA B57 gene have autoimmune problems: Their T cells are more likely to bind strongly to human peptides not encountered in the thymus.

The computational studies explained many puzzles, but also made a prediction: Individuals with HLA genes that result in a display of fewer self-peptides should control HIV (and other viruses like hepatitis C virus) better. To test this prediction, the researchers studied nearly 2,000 patients -- 1,100 "HIV controllers" and 800 who progressed normally to AIDS, and confirmed that this appears to be true.

New Path to Therapeutic HIV Vaccine Discovered by Studying Immunologic Profile of Rare HIV Controllers. 17/3/10

Vacc-C5 to Move From Lab to Phase I/II Clinical Trial

OSLO, NORWAY-- Based on encouraging results from pre-clinical research, Bionor Immuno AS today announced intentions to take the therapeutic and potentially preventative HIV-vaccine candidate Vacc-C5 into a Phase I/II clinical trial. The research results indicate that Vacc-C5 may induce a protective antibody response in HIV patients similar to that found in patients with slow or non-progressing disease.

"The very slow or non-progressing HIV infection observed in a small minority of patients, often referred to as 'controllers' because of their ability to live symptom-free with HIV, has been the subject of academic interest for years. The discovery of these antibodies in such patients could lead to a significant shift in the approach to treating HIV. The results have been presented to the Company's Clinical Advisory Board and with very encouraging feedback," said Birger Sørensen, CEO of Bionor Immuno. 

Vacc-C5 is the second vaccine in Bionor's pipeline. Vacc-4x, acting by a different mechanism (cell mediated immunity), has undergone a multi-centre placebo-controlled Phase IIB trial with 134 HIV-patients who have temporarily stopped taking daily ART. Results from the study are expected in October 2010.

Researchers Discover Vacc-C5 after Studying Immune Response of HIV Controllers

From research on blood donated by patients with a slow or non-progressing HIV disease, the Company has identified a specific part of the virus, C5, which is believed to induce hyper-activation of the immune system. Researchers believe that the antibodies to C5 are likely to be protective and cause a slow disease progression. Using its proprietary platform technology, the Company has developed Vacc-C5, which is designed to induce a similar antibody response to the one discovered in patients with slow disease progression. Vacc-C5 has passed pre-clinical research tests showing that it has the potential to induce the desired antibodies.

Disease progression from HIV to AIDS is triggered by the hyper-activation of the immune system. This hyper-activation overwhelms the immune system and gradually causes a collapse in the immune system, leading to AIDS. Researchers hope that Vacc-C5 will have the ability to stop or greatly slow this progression.

The antibodies induced by Vacc-C5 are expected to be beneficial at all stages of HIV disease and can be used for both treatment and prevention. Vacc-C5 works by halting the hyper-activation of the immune system, producing a dual effect; i) slowing down or halting the disease progression and ii) significantly reducing the production of the virus. These properties, in combination with the properties of the Company's most advanced vaccine candidate, Vacc-4x, may form a potent preventative HIV vaccine.

Clinical Trial Program Strategy
As part of the preparations for a Phase I/II clinical trial to be initiated in Q2, 2011, the Company will carry out routine toxicity tests, to ensure the safety of the Vacc-C5 components. The toxicology program is planned to be completed by early 2011.

Following the decision to move Vacc-C5 forward towards clinical testing the Company has placed an order with Bachem for the production of pharmaceutical-grade vaccine components to be used in the upcoming trial.

The HIV-market
In 2008 the United Nations estimated 33.4 million people are living with HIV globally, of which 2.14 million have access to highly effective treatment. The latter have access to antiretroviral therapy at a cost of between US$12,000 to $15,000 per year, per patient. Data monitor estimates the value of antiretroviral sales in the seven major markets (France, Germany, Italy, Japan, Spain, UK and USA) at US$11.7 billion. The antiretroviral therapy must be administered at precise intervals during the day and often cause adverse side effects.

About Bionor Immuno
Bionor Immuno is an innovative biotech company developing synthetic peptide vaccines that stimulate cell-mediated immunity. Previous efforts made to use T-cell stimulation for vaccines have been notoriously unsuccessful and this is the reason they are not on the market today. Bionor Immuno carefully designs synthetic (modified) peptides with improved efficacy and safety profiles. Among the diseases targeted are chronic infections such as HIV, Hepatitis C (HCV), Human Papilloma Virus (HPV) and Influenza. Bionor Immuno's platform technology is broadly applicable and makes it possible to extend the range of projects to include vaccines targeting cancer. More information is available at www.bionorimmuno.com. Bionor Immuno AS is a wholly owned subsidiary of Nutri Pharma ASA. Nutri Pharma ASA is listed on the Oslo Stock Exchange under the ticker symbol "NUT." More information is available at www.nutripharma.com.

Non-Stick Coating of a Protein Found in Semen Reduces HIV Infection. 23/9/10

The new material is a potential ingredient for microbicides

A non-stick coating for a substance found in semen dramatically lowers the rate of infection of immune cells by HIV a new study has found.

The new material is a potential ingredient for microbicides designed to reduce transmission of HIV, a team from the University of Rochester Medical Center and the University of California, San Diego reports in a forthcoming issue of the Journal of Biological Chemistry.

The coating clings to fibrous strings and mats of protein called SEVI-for semen-derived enhancer of viral infection-which was first discovered just three years ago. SEVI seems to attract the virus and deposit it onto the surface of T-cells, components of the immune system that are the primary target of HIV infection, and may play an important role in sexual transmission of HIV.

Like the fibrous strings that bind senile plaques associated with Alzheimer's disease, SEVI is a kind of protein superstructure called an amyloid.

Jerry Yang, associate professor of chemistry at UC San Diego and his research group developed non-stick coatings for amyloids as a potential treatment for Alzheimer's disease in 2006. Their idea was to minimize damage by preventing amyloid proteins from interacting with other molecules in the brain.

When this new amyloid, SEVI, was discovered in 2007, Yang was interested in testing whether the coating strategy might interfere with SEVI's role in promoting HIV infection.

Yang's group teamed up with a researchers led by Stephen Dewhurst, chair of the microbiology and immunology department at the University of Rochester Medical Center, who studies HIV.

"We tested one of our molecules out on SEVI and found it was able to stop SEVI-enhanced infection of HIV in cells," Yang said. "It works in semen too. Something in semen enhances viral infection -- SEVI and maybe other things. This molecule stops that."

When the researchers added the molecule that forms non-stick coatings to a mix of SEVI, virus and cells, rates of infection dropped to levels observed when SEVI was absent. They saw a similar effect with semen as well, evidence that this potential microbicide supplement works to inhibit infection within a mixture of proteins and other molecules found in seminal fluid.

The coating molecule is a modified form of thioflavin-T, a dye that stains amyloid proteins. It fits in between the individual small proteins that cluster to form SEVI and blocks SEVI's interactions with both the virus and the target immune cells.

"Other people have tried to do the same thing by targeting the virus or the cells it infects. What we do is target the mediator between the virus and the cells," Yang said. "By neutralizing SEVI, we prevent at least one way for HIV to attach to the cells."

The new molecule has another advantage. Unlike many current microbicide candidates aimed at reducing HIV infection, this one doesn't cause inflammation in cervical cells.

"Recent studies have shown for the first time that a topical microbicide gel can protect women from HIV-1 infection. This is a huge step forward but not a perfect solution. We need to figure out ways to further improve protection -- and our studies suggest one way of doing so," said Dewhurst, who is the corresponding author of the report. "It may be possible to produce a next-generation microbicide that includes both an antiviral agent, as has been used in the past, and an agent that targets SEVI. We're very excited about exploring this idea."

The National Institutes of Health and the National Science Foundation funded this work.

Additional co-authors include Joanna Olsen, Caitlin Brown, Todd Doran, Rajesh Srivastava, Changyong Feng and Bradley Nilsson of the University of Rochester, and Christina Capule and Mark Rubinshtein of the University of California, San Diego

Novel Sensing Mechanism Discovered In Dendritic Cells To Increase Immune Response To HIV. 9/9/10

Dendritic cells are the grand sentinels of the immune system

Dendritic cells are the grand sentinels of the immune system, standing guard 24/7 to detect foreign invaders such as viruses and bacteria, and bring news of the invasion to other immune cells to marshal an attack. These sentinels, however, nearly always fail to respond adequately to HIV, the virus causing AIDS. Now a team of scientists at NYU Langone Medical Center has discovered a sensor in dendritic cells that recognizes HIV, spurring a more potent immune response by the sentinels to the virus. They report their findings in the September 9, 2010, issue of Nature.

"This is the first time that an alarm system that recognizes retroviruses like HIV has been discovered," says Dan Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Departments of Pathology and Microbiology at NYU Langone Medical Center and a Howard Hughes Medical Institute investigator, and the study's lead author.

"The ability to stimulate a protective immune response against HIV is critical to the development of therapeutic or preventive vaccines for the virus," says Dr. Littman. In contrast to normal vaccines, which prevent infection, therapeutic vaccines are designed to boost the severely weakened immune systems of people infected with HIV.

Dendritic cells, named for their branching, tree-like shape, have been called the maestros of the immune system because they orchestrate a dynamic range of immune responses. These cells have attracted intense interest from researchers in many fields because of their potential to fight disease and prevent rejection of organ transplants.

When a dendritic cell captures a dangerous pathogen, it tears it apart and delivers a piece to the soldiers of the immune system cells, called T-cells, which in turn expand like a clonal army to coordinate immune defenses and destroy the invader. But dendritic cells fail to recognize HIV as a danger. Instead, HIV exploits the cells to get a free ride to T-cells, which become infected with the virus. "The virus actually infects the same soldiers that are supposed to protect us from it," explains co-author Derya Unutmaz, MD, associate professor in the Departments of Microbiology, Pathology and Medicine at NYU Langone Medical Center.

Although HIV enters dendritic cells, an unknown mechanism blocks the virus from infecting them going into the nucleus of the cells to make copies of itself. Recently, a technique was discovered to overcome this block by bathing the cells with a protein derived from SIV, a relative of HIV that only infects monkeys. Using these techniques, the researchers discovered that when HIV was forced to enter the nucleus of dendritic cells, the cells unexpectedly recognized the virus as an intruder and went into action to initiate a program to stimulate a stronger T-cell response against the virus

What set off the alarm, the researchers found, was a protein called capsid, which encapsulates HIV's genetic material. "It's surprisingly unexpected that the sensing mechanism of the dendritic cell recognizes the capsid of the virus, rather than the genetic material inside," says co-author Nicolas Manel, PhD, of The Kimmel Center for Biology and Medicine at the Skirball Institute at NYU Langone Medical Center and the Institut de Genetique Moleculaire de Montpellier. "Nevertheless, by adding elements of this capsid to a vaccine," says Dr. Manel, "it may be possible to improve the immune response of those who already have HIV or actually mount a potent immune response before the individual is infected."

"We still don't understand why this sensor is triggered only when we force HIV to integrate into dendritic cell genome to make its own copies," adds Dr. Unutmaz. "One possibility is that this cryptic sensing mechanism has evolved to recognize the thousands of ancient retroviruses that have infected us in the past and now make up almost 10% our genome. It is conceivable that dendritic cells have evolved this internal sensor in case any of these archaic retroviruses were reawakened. Nonetheless, the finding is extremely exciting because not only it could lead to new directions in HIV vaccine research but it can also be exploited to enhance vaccines against other viruses.”

Co-authors of the study include Brandon Hogstad, Yaming Wang and David E. Levy of NYU Langone Medical Center.

The study was funded by EMBO and Cancer Research Institute fellowships, by the Institut National de la Sante et de la Recherche Medicale, by the Howard Hughes Medical Institute, the Helen and Martin Kimmel Center for Biology and Medicine, and the National Institutes of Health in Bethesda, Maryland, and grants from National Institute of Health divisions of Allergy and Infectious Diseases.

Potential HIV Drug Keeps Virus out of Cells. 24/8/10

Ability to block the virus from infecting new cells

Following up a pioneering 2007 proof-of-concept study, a University of Utah biochemist and colleagues have developed a promising new anti-HIV drug candidate, PIE12-trimer, that prevents HIV from attacking human cells.

Michael S. Kay, M.D., Ph.D., associate professor of biochemistry in the University of Utah School of Medicine and senior author of the study published on Aug. 18, 2010, online by the Journal of Virology, is raising funds to begin animal safety studies, followed by human clinical trials in two to three years. Kay believes PIE12-trimer is ideally suited for use as a vaginal microbicide (topically applied drug) to prevent HIV infection. His research group is particularly focused on preventing the spread of HIV in Africa, which has an estimated two-thirds of the world's 33 million HIV patients according to the World Health Organization.

"We believe that PIE12-trimer could provide a major new weapon in the arsenal against HIV/AIDS. Because of its ability to block the virus from infecting new cells, PIE12-trimer has the potential to work as a microbicide to prevent people from contracting HIV and as a treatment for HIV infected people. HIV can develop resistance rapidly to existing drugs, so there is a constant need to develop new drugs in hopes of staying ahead of the virus." Kay said.

PIE12-trimer was designed with a unique "resistance capacitor" that provides it with a strong defense against the emergence of drug-resistant viruses.

Peptide drugs have great therapeutic potential, but are often hampered by their rapid degradation in the body. D-peptides are mirror-image versions of natural peptides that cannot be broken down, potentially leading to higher potency and longevity in the body. Despite these potential advantages, no D-peptides have yet been developed.

PIE12-trimer consists of three D-peptides (PIE12) linked together that block a "pocket" on the surface of HIV critical for HIV's gaining entry into the cell. "Clinical trials will determine if PIE12-trimer is as effective in humans as it is in the lab," Kay said.

Across the world, HIV occurs in many different strains and has the ability to mutate to resist drugs aimed at stopping it. Due to the high conservation of the pocket region across strains, PIE12-trimer worked against all major HIV strains worldwide, from Southeast Asia and South America to the United States and Africa.

To help advance toward human clinical trials, Kay and co-authors Brett D. Welch, Ph.D., and Debra M. Eckert, Ph.D., research assistant professor of biochemistry, formed a company, Kayak Biosciences, which is owned by the University of Utah Research Foundation. If PIE12-trimer proves to be an effective and safe drug against HIV, the same D-Peptide drug design principles can be applied against other viruses, according to Kay. Approval of the first D-peptide drug would also greatly stimulate development of other D-peptide drugs.

The study's first authors are Welch, and U of U graduate student J. Nicholas Francis. Also contributing were U graduate students Joseph Redman and Matthew Weinstock, as well as Eckert. Images of how PIE12 binds to the HIV pocket were obtained using X-ray crystallography, a technology that provides high-resolution analysis of atomic structures, and were provided by Frank Whitby, Ph.D., research assistant professor of biochemistry, and Christopher P. Hill, Ph.D., professor and co-chair of the Department of Biochemistry. The study includes colleagues from Thomas Jefferson University in Philadelphia and Monogram Biosciences, South San Francisco, Calif.

Rare Hybrid Cell Key to Regulating the Immune System. 24/5/10

"This is actually the first cell we know of that has this type of appearance in nature"

A cell small in number but powerful in its ability to switch the immune system on or off is a unique hybrid of two well-known immune cell types, Medical College of Georgia researchers report.

"This is actually the first cell we know of that has this type of appearance in nature," Dr. Andrew Mellor, molecular geneticist and immunologist who co-directs MCG's Immunotherapy Discovery Institute, said of the cell that looks like a dendritic cell and a B cell but isn't really either.

The discovery of this rare hybrid could have implications for the efficacy of new therapies that manipulate these two cell types to treat diseases such as cancer and rheumatoid arthritis.

When MCG scientists first reported the human equivalent of this cell in Science in 2002, they called it a subset of the dendritic cell that clusters in high exposure areas such as the gut but also roams the body, looking for invaders like a virus or cancer. Dendritic cells show their find to T cells, telling them to ignore or attack by bringing trash-eating macrophages, natural killer cells and the like into the fight.

What seemed most unique about the subset is its ability to express indoleamine 2,3 dioxygenase, or IDO, to turn off T cells. IDO is an enzyme used by fetuses and tumors alike to escape the immune response.

The new studies show that is only part of the cells' distinctiveness. The cells also have the identifying markings of B cells, known for their ability to make antibodies against invaders. In fact, they found the IDO-presenting cells came from the same precursor cell as B cells. But, when the scientists looked at mice missing B cells, they still found the IDO-producing cells. Hence, the cell didn't need to produce antibodies to turn off T cells.

In reality, IDO-expressing cells have properties of both cells, said Burles A. Johnson III, an MCG M.D.-Ph.D. student and first author of the paper published in the Proceedings of the National Academy of Sciences. "It looks like a B cell and it's not. It looks like a dendritic cell and it is and it isn't," Johnson said.

While their studies are in mice, the cells also are in humans, showing up in some unfortunate places such as the drainage system for tumors, melanoma or even HIV where they likely help the diseases survive.

They also may be showing up in new dendritic cell therapies designed to strengthen the immune response to cancer. If the therapies happen to include some IDO-expressing cells, those could end up helping the cancer, said Mellor, the paper's corresponding author. "All you need is a few of these cells in your dendritic cell vaccine and you don't get stimulation any more, you get suppression," Mellor said.

Their confusing face could also cause hybrids to be lost in B cell-depleting therapies designed to lessen the immune system's attack on joints in rheumatoid arthritis. "These therapies may also deplete IDO-expressing cells and decrease therapy effectiveness because you are eliminating cells that are there to help you," Johnson said.

"This gives us new insight into why these therapies might not be working as well as we think they might," Mellor added. Long-term goals include figuring out how to manipulate the hybrid's activity to benefit patients.

The research was funded by the National Institutes of Health and the Germany-based pharmaceutical company Boehringer-Ingelheim. Mellor is a Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics.

Science Unravels Resistance to HIV. 6/5/10

People who are resistant to HIV, the virus that causes Aids, have a gene that gives them a stronger immune system, a new study shows.

People who are resistant to HIV, the virus that causes Aids, have a gene that gives them a stronger immune system, a new study shows.

A small number of people exposed to HIV - about one in every 200 infected - develop Aids very slowly, or never develop the disease. Previous research found that a large number of these naturally HIV-immune people have a gene called HLA B57.

In this new study, US researchers found that HLA B57 causes the body to produce more powerful killer T-cells, which are white blood cells that attack infectious invaders. People with HLA B57 have a larger number of T-cells that bind strongly to more pieces of HIV protein than people who don't have the gene. In people with HLA B57, T-cells are more likely to recognise cells that express HIV proteins, including mutated versions that arise during infection.

The findings may help scientists develop vaccines that trigger the same immune response to HIV that occurs naturally in people with HLA B57, according to the researchers from the Ragon Institute of Massachusetts General Hospital, MIT and Harvard.

Scientists Discover Anti-HIV Molecule That May Prevent Infection. 04/01/10

Newly discovered molecule may block HIV transmission in the future

A team of American scientists has discovered a molecule that could block transmission of HIV, the virus that causes AIDS.  Researchers say the preventive agent might someday be used in a topical cream to help prevent infection with the deadly virus.

Scientists have long known that after the HIV virus enters the human body, it struggles to gain a foothold.  But a naturally occurring protein in the male's seminal fluid, called SEVI, makes the virus 100-thousand times more infectious than it would otherwise be, aiding HIV's ability to attach itself to its victim's white blood cells and in so doing, destroy the host immune system.

Now, US investigators have discovered that a molecule called surfen can interfere with SEVI's action. Warner Greene is the director of the Gladstone Institute of virology and immunology in San Francisco, California, where the test-tube studies have been conducted.

"What we have found is this small molecule by the name of surfen can block SEVI binding to HIV virions [viruses] and thus interrupt the infectious cycle or the transmission cycle," said Warner Greene.

Greene says surfen, first described by scientists back in 1939, is both an anti-inflammatory and anti-bacterial agent. He explains that surfen prevents infection by binding itself to both the AIDS virus and to the blood cells targeted by HIV.

Research into topical medications know as microbicides - creams and gels containing anti-HIV agents that are usually applied before sexual intercourse - has been disappointing, and the method has not been effective preventing the spread of the AIDS virus.  But Greene is hopeful surfen will make a difference.

"I think that the concept of using agents that target not only the virus but the host factor propelling the virus infection - I think that combination might produce a therapeutic synergy [enhanced interaction] that could be quite effective," he said.

Greene says similar so-called "cocktail" therapies have proved to be effective weapons in treating AIDS patients.

"Just as we use combination anti-retroviral therapy to treat patients with HIV infection, we might be able to prevent transmission of HIV using combination microbicides," said Greene.

Warner Green and colleagues describe surfen's anti-AIDS properties in the current issue of the Journal of Biological Chemistry.

Scientists Discover Antibody for HIV. 12/7/10

Researchers have discovered a protein that can protect against a wide range of HIV

AllAfrica

Researchers have discovered a protein that can protect against a wide range of HIV, and said they may now be able to finally design a vaccine against the fatal and incurable virus.

The proteins called antibodies are used by the body's defence system to identify and neutralise foreign objects, such as bacteria and viruses.

"I am more optimistic about an Aids vaccine at this point than I have been probably in the last 10 years," Dr Gary Nabel of the US National Institute of Allergy and Infectious Diseases, who led the study, said in a telephone interview.

Two of the antibodies can attach to and neutralise 90 per cent of the various mutations of the human immuno-deficiency virus that causes Aids, Nabel said.

There are two main types of the virus: HIV-1 and HIV-2 with the most prevalent in Kenya being the former. HIV-1 is classified into four groups which further fall into several sub-types.

These different strains make it difficult to produce a vaccine that could protect an individual from the virus, mainly because of what is called super infection or co-infection.

This means that a person already carrying the virus can be infected with a different strain. This indicates that a vaccinated person against one strain is not protected against all other strains.

Current approaches also mean researchers have to spend a lot of time and resources testing vaccine for various strains in trials tested in many different localities where differing strains are found.

Theoretically, the new find is the proverbial "hitting many birds with one stone". Using one vaccine candidate, tested in only one location could mean offering a blanket cover against the virus.

The virus is difficult to fight in part because it attacks immune system cells and in part because it mutates constantly, making it a moving, ever shifting target for drugs or the immune system.

It has been almost impossible to make a vaccine that will affect the virus.

Last September, researchers reported their biggest success yet with a vaccine that appeared to slow down the rate of infection by about 30 per cent among Thai volunteers, but the trial left many questions unanswered.

Researchers have been looking for parts of the virus that do not mutate, so they can design a vaccine that will protect against these constantly changing versions.

Nabel's team found two of the antibodies in the blood of a patient infected with HIV who had not become ill despite the infection.

Such people are called non-progressors, and researchers study their immune systems to find out why they control the virus better than most patients. They then found the immune system cells called B-cells that made these particular antibodies, using a new molecular device that they invented.

In yet another experiment, they managed to freeze one of the antibodies in the process of attaching to and neutralising the virus, getting an atomic-level image in a process called x-ray crystallography.

Being able to "see" what the structure looks like could enable researchers to design a vaccine using a process called rational vaccine design, akin to an established technique for making drugs called rational drug design, Nabel said.

It may also be possible to design gene therapy to help patients make these antibodies themselves, or use an older technique that transfuses the antibodies directly.

One of the antibodies, called VRC01, partially mimics the way an immune cell called a CD4 T-cell attaches to a piece of the Aids virus called gp120, the researchers said.

"The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralise such an extraordinary range of HIV strains," Dr John Mascola, who worked on the study, said in a statement.

"The discovery of these exceptionally broadly neutralising antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use," NIAID director Anthony Fauci added in a statement.

"In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases."

Scientists Seek HIV Clues. 13/7/10

Scientists in Nairobi have reported success in identifying three Kenyans whose immune system could hold the key to finding an HIV vaccine.

AllAfrica

Nairobi — Scientists in Nairobi have reported success in identifying three Kenyans whose immune system could hold the key to finding an HIV vaccine.

The researchers spoke a day after their colleagues at the US National Institute of Allergy and Infectious Diseases announced that they had isolated an antibody that can protect a person from numerous strains of the Aids-causing virus.

Recently, Prof Omu Anzala, a University of Nairobi lecturer and Kenya Aids Vaccine Initiative (Kavi) director, said his team had identified the three with promising broadly neutralising antibodies.

Prof Anzala says these antibodies, isolated by Kavi and the International Aids Vaccine Initiative (IAVI) can disable 90 per cent of the HIV strains.

"This is the most exciting part of it; the ability of these antibodies to neutralise a wide range of the HIV strains," he said.

The virus type predominant in Kenya is HIV-1, whose strains can be classified into groups M, N, O and P. Group M has subtypes A, B, C, D, F, G, H, J and K.

Subtypes A, C, D, and G are some of those circulating in Kenya.

Of the more than 200 people that have been followed by Kavi for several years, the latter subtypes have emerged as instrumental in the future development of a broadly neutralising antibody vaccine.

"So far, we have managed to isolate few individuals who have very promising results and now they are being studied to understand how their immune system is able to neutralise the virus," says Prof Anzala, a virologist.

The ability to disable the HIV virus is being seen in both men and women whom Kavi has been studying for several months.

Scientists strongly believe with such the ability to stop the virus from infecting new cells, the people could hold the key to developing an effective Aids vaccine. Studies in primates have already shown that the anti-bodies can prevent HIV infection.

Those with such antibodies and who are able to stave off HIV replication in their bodies have come to be known as the elite controllers -- those whose immune system can control the HIV viral load to less than 40 copies/mL, compared to over 30,000 in a person without such antibodies.

Stem-Cell Work Closes a Door to AIDS. 3/7/10

CCR5 proteins prevents most strains of HIV from infecting the cell.

Paris - Lab work on mice has opened up a novel way of closing a gateway to the Aids virus, according to a study published on Friday.

The doorway in question is called CCR5, a protein that helps the human immunodeficiency virus (HIV) penetrate a cell, its first step before hijacking the cellular machinery and reproducing itself.

Around a decade ago, scientists discovered that people who had a tiny gap in the genetic code for making CCR5 were surprisingly resistant to HIV infection and took more time to progress to AIDS.

This gene variant, known as CCR5 delta 32, results in smaller CCR5 proteins, which prevents most strains of HIV from infecting the cell.

Testing a theory, scientists in the United States took immature haematopoietic cells - which make immune and red blood cells - from mice.

They modified some of the cells, using a brand-new enzyme "cutter" to delete the famous CCR delta 32 section.

As a result, when these cells matured and divided, they lacked the key code for making normal CCR5.

The modified cells were reinjected back into the rodents, which were then exposed to HIV. Twelve weeks after infection, the animals had recovered their stock of immune T-cells and their levels of HIV were very low.

But "control" mice that had not received the modified cells were highly infected and their immune systems weak.

If the approach is found to be safe and effective on humans, it opens the way to creating a long-term generation of HIV-resistant T-cells in the body - in other words, a patient could suppress HIV without taking powerful antiretroviral drugs.

The experiment headed by Paula Cannon of the University of Southern California, Los Angeles, and reported in the journal Nature Biotechnology, is the third avenue that has opened up for CCR5 investigators .

Drugs that inhibit CCR5 are already being licensed as "salvage" therapy for patients whose immune systems have been crippled by HIV.

Doctors are also testing in trials on volunteers a CCR delta 32 technique, but using T-cells as opposed to stem cells.

Around two million people died from Aids in 2008, and 33.4 million were living with HIV, according to UN figures published last November.

The International AIDS Conference, an event held once every two years, takes place in Vienna from July 18-23.

Structure of Immune Molecule that Counteracts HIV Strains Determined. 3/6/10

"This study advances the overall goal of how to design an HIV vaccine"

In findings that contribute to efforts to design an AIDS vaccine, a team led by Scripps Research Institute scientists has determined the structure of an immune system antibody molecule that effectively acts against most strains of human immunodeficiency virus (HIV), the virus that causes AIDS.

The study, which is being published in an advance, online issue of the journal Proceedings of the National Academy of Sciences (PNAS) during the week of June 1, 2010, illuminates an unusual human antibody called PG16.

Most of the antibodies that the body produces to fight HIV, however, are ineffective. The surface of the virus is cloaked with sugar molecules that prevent antibodies from slipping in and blocking the proteins the virus uses to latch onto a cell and infect it. To make matters more complicated, HIV is constantly mutating, so there are multiple HIV strains that antibodies elicited in any vaccine must be able to sense and destroy.

In x-ray crystallography, scientists manipulate a protein or some other molecule so that a crystal forms. This crystal is then placed in front of a beam of x-rays, which diffract when they strike the atoms in the crystal. Based on the pattern of diffraction, scientists can reconstruct the shape of the original molecule. The scientists succeeded in forming crystals of the active part of the PG16 antibody, and in reconstructing the structure from the data -- with some surprising results.

"The antibody has a novel and really interesting subdomain that hasn't been seen before," said Research Associate Rob Pejchal, who is first author of the paper. "This subdomain, which we found plays a major role in the recognition and neutralization of HIV, has a different kind of antibody architecture. We like to call it the 'hammerhead' because it resembles the head of a hammerhead shark. It reaches out from the main part of the antibody and it has two flat ends on top."

Co-author Laura Walker, a graduate student in the Scripps Research Kellogg School of Science and Technology, added, "This hypervariable loop (CDR3) that forms the novel subdomain is also unusually long for an antibody. Almost all of the antibodies we know to be broadly neutralizing against HIV have one unusual feature or another."

Pejchal notes that the study also revealed that PG16 was sulfated, suggesting possible mechanisms of action not usually seen in antibodies this effective against HIV.

While the scientists were unsuccessful so far in crystallizing PG16's sister molecule PG9, they were able to glean insight into its action from biochemical studies using both molecules. By switching a small (seven-amino acid) segment of the CDR3 subdomain of PG9 for a similar segment from PG16, the team changed the subset of HIV isolates neutralized by the antibody. This confirmed the loop in question was the "business end" of the antibody and suggested that it might be possible to create other interesting variants of the antibody by manipulating this region.

Seth Berkley, president and CEO of IAVI, which funded the study with the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institute of Health (NIH), noted, "These studies of PG16 have taught us a lot about how these neutralizing antibodies work. I am particularly excited by the possibilities these findings open up for AIDS vaccine development, since the breadth and potency of HIV neutralization achieved by PG16 is what we'd like to see in the antibodies elicited by a vaccine. IAVI and its researchers will continue to support the application of these findings to the design of novel immunogens against HIV. We hope that we will be able to translate the insights gleaned from this study into the design of a promising AIDS vaccine candidate."

In addition to Wilson, Burton, Pejchal, and Walker, authors of the paper are Robyn Stanfield and Pascal Poignard of Scripps Research and IAVI, Wayne Koff and Sanjay Phogat of IAVI New York. This study was supported by IAVI, NIAID, the Skaggs Institute of the Scripps Research Institute, and the Ragon Institute.

Study in Elite who Control HIV Without Drugs Points Way for Vaccine. 5/5/10

This study found that people with the HLA B57 gene were more likely to generate killer T-cells which could react to several different HIV proteins, or epitopes.

AIDSMap

Research in people who have controlled HIV at very low levels for years without drugs has revealed that a human genetic trait linked to autoimmunity may point the way to an effective vaccine against HIV, researchers from Boston report today in the online edition of the journal Nature.

A very small proportion of people (around 0.5%) who become infected with HIV experience little or no disease progression, and maintain a viral load that is near to undetectable for many years.

Scientists led by Professor Bruce Walker of Massachusetts General Hospital have been recruiting these 'elite controllers' of HIV for the past four years with the aim of studying how their immune systems control HIV.

The newly-published study looked at one common feature of many 'elite controllers', a genetic mutation called HLA B57, which is also associated with autoimmune conditions in which immune cells can attack the host’s own proteins because they are not recognised as 'self'.

This study found that people with the HLA B57 gene were more likely to generate killer T-cells which could react to several different HIV proteins, or epitopes. This means that even if one epitope mutates to escape the virus, the killer T-cell can still bind strongly to other viral epitopes, increasing the chance that the virus will be eliminated.

The HLA B57 gene appears to confer this advantage through less rigourous screening of 'self'-reactive T-cells in the thymus, the organ through which they pass in order to become mature T-cells.

They are less likely to be tested against 'self' proteins in the thymus, and so even if 'self'-reactive, less likely to be weeded out at this stage.

Once in circulation, they have a stronger ability to bind to HIV proteins

The finding offers hope that researchers could design a vaccine to help draw out cross-reactive T-cells in people who don’t have the HLA B57 gene. “It’s not that they don’t have cross-reactive T-cells,” said Professor Arup Chakraborty of Massachusetts Institute of Technology, “they do have them, but they’re much rarer, and we think they might be coaxed into action with the right vaccine.”

Reference
Kosmrlj A et al. Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection. Nature (advance online publication, May 5, 2010).

Using ARVs for Prevention. 24/5/10

Using antiretrovirals in microbicides as an effective HIV prevention method specifically aimed at women is in the spotlight at the Microbicides 2010 conference currently underway in the United States.

Health-e

Pittsburgh, USA – Using antiretrovirals in microbicides as an effective HIV prevention method specifically aimed at women is in the spotlight at the Microbicides 2010 conference currently underway in the United States.

Trials currently underway include CAPRISA 004, a collaborative study between Family Health International, the Centre for the AIDS Programme of Research in South Africa (CAPRISA) at the University of KwaZulu-Natal, and US-based CONRAD. The study is taking place in Durban and is assessing the effectiveness of a gel containing tenofovir, a widely used ARV.

The results of the study will be presented at the International AIDS conference in Vienna, Austria in July this year.

Another study was the Vaginal and Oral Intervention to Control the Epidemic (VOICE) which started last year and is also testing the effectiveness of tenofovir in a vaginal gel compared to a tenofovir tablet taken orally.

The VOICE study will also inform the CAPRISA 004 study as to whether women prefer a tablet or a gel.

Nomfundo Eland from the Treatment Action Campaign said there was a need for improved delivery systems alongside scientific research.

“Research and science alone will not win the fight on new infection but we will win when combined strategies to address behaviour, gender inequality, economic status of women and access to prevention tools owned by women are available,” Eland told the conference.

She said it was critical to engage communities and to get communities informed on the various prevention methods and trials taking place within their vicinity.

“We need to know who our allies in this work are. For example, I was recently addressing one of the biggest and most influential workers’ unions in SA - where no-one knew of any prevention trials happening in the country until the world makes noise about “failed trials” in their backyard,” she said.

She said issues such as stigma, policies that discriminate against those infected with HIV, sexual discrimination and funding cuts continued to pose a threat in the success of prevention methods.

Vuyiseka Dubula, General Secretary, Treatment Action Campaign urged researchers to persevere amidst the challenges.

“I know that there is a lot of negativity on prevention biomedical research due to many microbicides studies being disappointing but we cannot give up. Activism without science is nothing and science without activism can only go so far. We need evidence to advocate for better tools for prevention,” she said.

Experts Analyze Immunity to AIDS. 16/11/09

Health researchers are gathering in Winnipeg today for a first-of-its-kind conference on an unusual topic -- people who DON'T get sick with AIDS.

Those people, a small but critical group who seem to enjoy a natural immunity to the deadly virus, could hold the key to a cure for AIDS, which has infected more than 33 million people.

"For the last 20 years, we've all kind of banged our heads against the wall trying to develop a vaccine for a virus that changes so often," said Keith Fowke, a medical microbiology professor at the University of Manitoba who also works out of the Public Health Agency of Canada's National Microbiology Lab. "This is what keeps a lot of us going. There is an answer."

About 75 of the world's top AIDS researchers -- scientists and doctors from as far away as Italy, Sweden and Kenya -- are gathering for the next two days at the Fort Garry Hotel to share what they know about people who don't get HIV/AIDS despite repeated exposure.

Officials hope the symposium, hosted by the International Centre for Infectious Diseases, the U of M, and the Public Health Agency of Canada, will help scientists pool data, share ideas and catapult the search for a cure forward.

Winnipeg researchers helped pioneer the field of study 20 years ago with research on Kenyan sex-trade workers who never developed the disease despite years of unprotected sex.

Since then, there's been research done on hemophiliacs who received tainted blood but never got sick, intravenous drug users and couples with one infected partner but another who remains healthy.

The trouble is, the sample sizes have always been too small for researchers to make conclusions and there's never been a national gathering of experts able to share their findings.

Fowke said he expects to see a vaccine for HIV/AIDS in his lifetime, and if it happens it won't be because of one isolated breakthrough, but because many researchers pooled their knowledge.

Fowke will present his research on the immune systems of Kenyan sex-trade workers, including the effects of the kind of unusually calm immune system the sex-trade workers seem to have. That may actually help a person fend off infection because there are fewer activated cells for the virus to target.

maryagnes.welch@freepress.mb.ca

33 million - Number of people living with AIDS worldwide

63,000 - Number of Canadians who tested positive for HIV between 1985 and 2007

1,500 - Number of Manitobans who tested positive between 1985 and 2007

 -- Public Health Agency of Canada and World Health Organization

HIV Eradication: One Step Closer. 13/10/09

Scientists Join Forces To Explain HIV Spread In Central And East Africa. 29/9/09

Genetic, geographic data deliver clear picture of HIV progress

GAINESVILLE, Fla.(Eureka Alert)—Scientists studying biology and geography may seem worlds apart, but together they have answered a question that has defied explanation about the spread of the HIV-1 epidemic in Africa.

Writing in the September issue of AIDS, a research team led by scientists at the University of Florida explained why two subtypes of HIV-1 — the virus that causes acquired immunodeficiency syndrome, or AIDS — held steady at relatively low levels for more than 50 years in west central Africa before erupting as an epidemic in east Africa in the 1970s.

Essentially, the explanation for the HIV explosion — obscured until now — involves the relative ease with which people can travel from city to city in east Africa as opposed to the difficulties faced by people living in the population centers of the Democratic Republic of Congo, the point where HIV emerged from west central Africa in its spread to the east.

Later, as the epidemic raged in the east, cities in the Democratic Republic of Congo — a vast country almost as big as all of Western Europe — remained disconnected and isolated, explaining why the virus affected only about 5 percent of the country's population, a level that has not changed much since the 1950s.

"We live in a world that is more interconnected every day, and we have all seen how pathogens such as HIV or the swine flu virus can arise in a remote area of the planet and quickly become a global threat," said Marco Salemi, an assistant professor of pathology, immunology, and laboratory medicine at the UF College of Medicine and senior author of the study. "Understanding the factors that can lead to a full-scale pandemic is essential to protect our species from emerging dangers."

Investigators used databases, including GenBank from the National Center for Biotechnology Information, as well as actual DNA samples, including samples recently collected in Uganda — the vicinity where HIV entered east Africa — to follow the virus' molecular footprints since its emergence in the 1920s.

"HIV mutates rapidly," said Rebecca Gray, a postdoctoral associate in the department of pathology, immunology and laboratory medicine. "This is a successful strategy for the virus, because it evolves quickly and develops drug resistance. But we can use these changes in the genome to follow it over time and develop a history of its progress."

Researchers wanted to know why, the virus smoldered during the 1950s and `60s, before spreading like wildfire through east Africa in the 1970s.

A fateful piece of the puzzle came in the form of geographic information system data, which uses satellite imagery and painstakingly takes into account the availability and navigability of roads between population centers, transportation modes, elevation, climate, terrain and other factors that influence travel.

"We were able to use geographic data to interpret the genetic data," said Andrew J. Tatem, Ph.D., an assistant professor of geography in the College of Liberal Arts and Sciences and a member of UF's Emerging Pathogens Institute. "Genetic data showed once HIV moved out of the Democratic Republic of Congo, it expanded fast and moved rapidly across Uganda, Kenya and Tanzania, all while staying at low levels in the DRC. What was happening was the virus was circulating at stable levels in the urban centers of the DRC, but these centers were isolated. Once it hit east Africa, connectivity between population centers combined with better quality transportation networks, and higher rates of human movement caused HIV to spread exponentially."

HIV was prevalent in about 15 percent of the population in Kenya in 1997, although it has since dropped to about 7 percent, according to the Kaiser Family Foundation. As of 2007, an estimated 22 million people were living with HIV/AIDS in sub-Saharan Africa. About 1.1 million Americans have HIV or AIDS, and an estimated 5.1 million people in India are HIV-positive. In Eastern Europe, HIV infections more than doubled from 420,000 in 1998 to 1 million in 2001.

"If we can predict the specific routes of an epidemic, we can find the geographic regions more at risk and target these areas with medical intervention and strategies for prevention," Salemi said. "In terms of health-care applications, coupling genetic analysis with geographic information systems can give us a powerful tool to understand the spread of pathogens and contain emerging epidemics."

Working with Maureen M. Goodenow, Ph.D., the Stephany W. Holloway university chair for AIDS research at the UF College of Medicine, UF researchers collaborated with an array of scientists hailing from the National Institute of Allergy and Infectious Diseases, the Rakai Health Sciences Program and Makerere University of Uganda, and the Johns Hopkins University. They refer to the combination of techniques that led to the discovery as "landscape phylodynamics."

"It is the first study that has given us a clear picture of epidemic history of HIV in east Africa, including the geographic routes and the time scale that it occurred," said Oliver Pybus, Ph.D., a researcher in the department of zoology at Oxford University who did not participate in the study. "Genetic analysis of the HIV genome provides the family tree of the virus, combined with spatial analysis of high-resolution data of land use, topology and other factors. There is a huge potential in doing that kind of analysis, but it requires a rare combination of specialists in different fields to come together."

Contact: John Pastor
jdpastor@ufl.edu
352-273-5815
University of Florida

How HIV Cripples Immune Cells. 16/9/09

Disease Mechanism in HIV Infection Decoded; Heidelberg Virologists Publish in Cell Host & Microbe

HIV and Bone Marrow Transplants. 09/09

Lyn's Comment: A person living with HIV also had leukaemia (a type of blood cancer). As treatment for his leukaemia, he required a bone marrow transplant, an expensive and potentially dangerous treatment.

Doctors know that some people have a gene mutation that helps the body resist HIV. (A gene mutation can be explained as a variation in the instruction part of cells.) Doctors chose one of these people as a donor for the bone marrow transplant.

Twenty months after this bone marrow transplant, no sign of the HI Virus can be found in the patient's body.

Although bone marrow transplants are too dangerous and expensive to become a general treatment option for HIV, it does open exciting new research options in gene therapy.

Read news reports on this development:

New Aids Virus Discovered. 02/08/09

2009-08-02

Washington - A new strain of the virus that causes Aids has been discovered in a woman from Cameroon.

It differs from the three known strains of human immuno-deficiency virus and appears to be closely related to a form of simian virus recently discovered in wild gorillas, researchers report in Monday's edition of the journal Nature Medicine.

The finding "highlights the continuing need to watch closely for the emergence for new HIV variants, particularly in western central Africa," said the researchers, led by Jean-Christophe Plantier of the University of Rouen in France.

Chimpanzees

The three previously known HIV strains are related to the simian virus that occurs in chimpanzees.

The most likely explanation for the new find is gorilla-to-human transmission, Plantier's team said. But they added they cannot rule out the possibility that the new strain started in chimpanzees and moved into gorillas and then humans, or moved directly from chimpanzees to both gorillas and humans.

The 62-year-old patient tested positive for HIV in 2004, shortly after moving from Cameroon to Paris, according to the researchers. She had lived near Yaounde, the capital of Cameroon, but said she had no contact with apes or bush meat, a name often given to meat from wild animals in tropical countries.

Cells

The woman currently shows no signs of Aids and remains untreated, though she still carries the virus, the researchers said.

How widespread this strain is remains to be determined. Researchers said it could be circulating unnoticed in Cameroon or elsewhere. The virus' rapid replication indicates that it is adapted to human cells, the researchers reported.

Their research was supported by the French Health Watch Institute, the French National Agency for Research on Aids and Viral Hepatitis and Rouen University Hospital.

Scientists Decode HIV Genome - HIV 'Missing Link' Found 6/8/09

News 24

Researchers Crack HIV Genome Structure 6/8/09

Poz.com

Scientists Discover New Strain Of HIV Closely Related To Simian Virus 03/08/09

 Scientists have discovered a new strain of HIV in a 62-year-old woman from Cameroon that "differs from the three known strains ... and appears to be closely related to a form of simian virus recently discovered in wild gorillas" according to a study in today's edition of the journal Nature Medicine, AP/Washington Times reports. The study was funded by the NIH and the Tietze Foundation (8/3). "The discovery of this novel HIV-1 lineage highlights the continuing need to watch closely for the emergence of new HIV variants, particularly in western central Africa, the origin of all existing HIV-1 groups," researchers note in the study (Reuters, 8/3). According to the AP/San Francisco Chronicle, the woman had no contact with gorillas or meat from wild animals and "currently shows no signs of AIDS and remains untreated, though she still carries the virus, the researchers said." The article adds, "How widespread this strain is remains to be determined. Researchers said it could be circulating unnoticed in Cameroon or elsewhere."

 A separate paper also in today's edition of Nature Medicine, "reports that people with genital herpes remain at increased risk of HIV infection even after the herpes sores have healed and the skin appears normal," according to the AP/Chronicle (Schmid, 8/3).

 Reprinted from kaisernetwork.org. You can view the entire Kaiser Daily HIV/AIDS Report, search the archives, and sign up for email delivery at www.kaisernetwork.org/dailyreports/hiv . The Kaiser Daily HIV/AIDS Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation. © 2009 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Scientists Find New Human HIV From Gorillas. 03/08/09

03 Aug 2009

Scientists who found a new human immunodeficiency virus (HIV) in a Cameroonian woman living in Paris, have discovered it is an unusual variant of HIV-1 that could have come from gorillas.

The research that led to the findings was headed by Dr Jean-Christophe Plantier of the University of Rouen in France and is published in the 2 August online issue of Nature Medicine. Drs David Robertson and Jonathan Dickerson from the Faculty of Life Sciences at The University of Manchester, UK, were also involved in the study.

There are three established lineages of HIV-1, known as M, N, and O, which came from chimpanzees, but this new variant appears to be the prototype of a new lineage derived from gorillas and shows no evidence of recombination with the other known lineages, wrote the researchers.

They propose that the new lineage be called HIV-1 group P.

There are 33 million people worldwide living with AIDS which is caused by the HIV-1 virus group M (groups N and O are mainly confined to Cameroon).

HIV is a product of cross-species transmission of Simian Immunodeficiency Virus (SIV) found in chimpanzees, thought to have crossed to humans from eating infected bush meat.

While first recognized in 1980, HIV is thought to have started some 80 years earlier in and around the African country that is now called the Democratic Republic of Congo.

The 62-year old Cameroonian woman at the centre of the study moved to Paris in 2004 and began to have symptoms shortly afterwards. Her blood sample showed discrepancies in her viral load, and further tests revealed she was infected with a new strain of HIV that more closely resembled SIV from gorillas than HIV from humans.

However, before moving to Paris the woman had lived in a semi-urban part of the central west African Republic of Cameroon; she had not come into contact with bush meat or gorillas.

Because of this information and the fact further tests showed that the virus was able to replicate in human cells, the scientists suggest the strain may well appear elsewhere.

Robertson told the media that:
"The discovery of this novel HIV-1 lineage highlights the continuing need to monitor closely for the emergence of new HIV variants."

"This demonstrates that HIV evolution is an ongoing process. The virus can jump from species to species, from primate to primate, and that includes us; pathogens have been with us for millions of years and routinely switch host species," he added.

In the same way as the current swine flu pandemic is showing us, this is another example of how viruses can now move very quickly around the world because nowadays large numbers of humans travel long distances in a short space of time.

Plantier's team in France are part of a network of laboratories that has been monitoring HIV genetic diversity, while the The Manchester Life Sciences team helped with the computer-based evolutionary analysis.

"A new human immunodeficiency virus derived from gorillas."

Jean-Christophe Plantier, Marie Leoz, Jonathan E Dickerson, Fabienne De Oliveira, François Cordonnier, Véronique Lemée, Florence Damond, David L Robertson & François Simon.
Nature Medicine, Published online: 02 August 2009.
DOI:10.1038/nm.2016

Scientists Discover HIV “Missing Link” in Primates. 23/07/09

POZ.COM

Scientist believe that a primate version of HIV—called simian immunodeficiency virus (SIV)—is killing the endangered African chimpanzee at a high rate, The Associated Press reports. It had previously been believed that chimps, like other primates in the wild, did not get sick from SIV.

The new discovery has been viewed as a missing link in the evolution of HIV, which may help researchers find a vaccine or cure for HIV.

According to the article, a nine-year study on chimps at Tanzania’s Gombe National Park discovered that the primates with SIV had a death rate 10 to 16 times higher than uninfected chimps. After looking at that particular strain of SIV, scientists found that it was similar to the virus that first infected humans.

While chimpanzees seem to be vulnerable to the virus, most monkeys and apes that have it often show no symptoms or illness. Daniel Douek, MD, of the National Institute of Allergy and Infectious Diseases, believes that an evolutionary adaptation on the cell receptors might have helped monkeys and apes survive SIV.

“From an evolutionary and epidemiological point of view,” Douek said, “these data can be regarded as a ‘missing link’ in the history of the HIV pandemic."

Finding Related To SIV In Monkeys Could Shed Light On HIV In Humans, Researchers Say 23/7/09

Kaiser Network  

Eradicating HIV From ‘Hiding Places'. 23/6/09

Lyn’s Comment: One of the dilemmas for effective treatment of HIV is the fact that the virus is not always reachable by existing drugs. The virus ‘hides’ inside immune cells that act as ‘HIV reservoirs’. Scientists have now identified the cells where HIV hides, and the methods the virus uses to escape existing treatments. This opens the way for research into new treatment options, where present treatment can be combined with specialised medication that targets these reservoir cells. Sadly, much more research is necessary before this will be usable in people living with HIV.

Mapping of AIDS Genome Portends Better Drugs 5/8/09

Canwest News Service

Wild Chimpanzees Get AIDS-Like Illness. 23/07/09

July 23, 2009

US researchers have shown for the first time that chimpanzees can fall ill and die from infection by the HIV-like simian immunodeficiency virus (SIV), overturning a decade-old consensus that chimps were immune to it. The discovery suggests that scientists will not find the solution to HIV immunity in the chimp genome. However, it sets the stage for comparative research, allowing scientists to see how humans and non-human primates respond differently to HIV and SIV infection.

"From an evolutionary and epidemiological point of view, these data can be regarded as a ?missing link' in the history of the HIV pandemic," said Daniel Douek of the National Institute of Allergy and Infectious Disease.

Beatrice Hahn of the University of Alabama-Birmingham and colleagues studied wild chimpanzee groups for nine years at Gombe National Park in Tanzania, collecting urine and fecal samples to analyze for SIV infection. The chimp groups had a 9-18 percent infection rate. Chimps that were infected were 10-16 times more likely to die than uninfected animals, and all infected infants died. Compared to uninfected chimps that died, those infected had unusually low CD4 T cells, the same cell type that HIV targets in humans.

In the wild, other primates such as monkeys have co-existed with SIV for a long time, seemingly by evolving an ability to control the virus. Rhesus macaques are not natural SIV hosts but can become ill from an infection. Comparative research on SIV and HIV in the different hosts could help in developing HIV treatments and vaccines, said Don Sodora, a viral immunologist with the Seattle Biomedical Research Institute at the University of Washington.

However, Hahn does not believe studies should extend to reversing the movement to stop invasive research on chimpanzees. "They think and have societies," she said. "Rather than shooting them up with SIV, one should be more creative and find ways and means of answering the question without doing harm to chimpanzees."

The full report, "Increased Mortality and AIDS-Like Immunopathology in Wild Chimpanzees Infected with SIVcpz," was published in Nature (2009;460:515-519).

Chimps Die From AIDS-Like Disease After Viral Infection 22/7/09

 AFP

AIDS-Like Illness Found In African Chimps - Finding Could Shed Light On How The Disease Affects Humans 22/7/09

Health Day

Natural Immunity Against HIV. 10/4/09

Natural immunity against HIV: a few needles in a haystack (Part 1)

Introduction
Over the years, several host genetic factors have been identified that may afford protection against HIV-1 infection or disease progression to AIDS. Individuals who show resistance to HIV-1 have been categorised broadly into two classes, namely those who, despite multiple known exposures to HIV-1, do not seroconvert (also known as highly exposed, seronegative (ESN) individuals), and those infected individuals who show no symptoms of AIDS, despite a long course of infection and without antiretroviral treatment (also known as long-term non progressors, LTNP)¹. Both ESN and LTNP have proven invaluable to researchers investigating the mechanisms of infection, although frequencies of genotypes conferring resistance to HIV-1 are low.

Chemokine receptors

CCR5
HIV uses CD4 and a co-receptor, most commonly the chemokine receptors CCR5 and CXCR4, to bind and enter cells. Single nucleotide polymorphisms (SNPs) in the CCR5 coding and regulating regions affect HIV-1 disease. Notably, a 32-bp deletion from the coding region of the CCR5 gene (Δ32) confers almost complete protection against HIV-1 infection when present in homozygous form (CCR5-32/Δ32), whereas individuals heterozygous for CCR5-wt/Δ32 show some resistance to infection with HIV-1, as well as a slower rate of disease progression. This deletion is absent in most African populations. Several SNPs in the regulatory region of the gene have been shown to alter the rate of disease progression to AIDS. Among these are variants in the promoter area at positions 59029 and 59353 that play an important role in mother-to-child-transmission (MTCT). Antiretroviral naïve infants with at least one 59029-A allele, conferring higher expression of CCR5, are at greater risk for MTCT than G/G homozygotes. However, upon exposure to nevirapine, A-allele carriers were less likely to be infected through MTCT, as opposed to increased risk of transmission when zidovudine were administered².

CCR2
A SNP in the coding region of CCR2 seems to slow HIV-1 disease progression in adults, but the role of this particular co-receptor remains uncertain due to conflicting data from different studies.

CXCR4
CXCR4 is often used as HIV-co-receptor in persons with more advanced disease, and this is also associated with more rapid disease progression. The natural ligand of CXCR4, SDF-1, seems to predispose carriers of the homozygous SDF1-3'-A/A genotype to more rapid disease progression than other variants of this SNP. However, this genotype seems to be rare in the population studied by Singh and Spector².

CX₃CR1
Another chemokine receptor, CX₃CR1, a receptor for fractalkine, has been shown to be an indicator of disease progression and related complications that may be used independently of CD4+ count and viral load. Expression of both CX₃CR1 and fractalkine are upregulated during HIV-1 infection, and reduced with effective antiretroviral therapy, suggesting a directing role in the immune response against HIV-1. CX₃CR1-M280-homozygotes have been shown to progress to AIDS more rapidly than individuals with other genotypes. Haplotypes I249-T280 and I249-M280 also tend to be associated with early immunological failure. Furthermore, in HIV-infected children, it has been shown that fractalkine is upregulated in the brain, but that greater binding of CX₃CR1 takes place in individuals with the wild-typeV/V249 genotype, as well as in heterozygotes (V/I249), resulting in slower disease progression when compared to I/I249 homozygotes. In children with the CCR5-wt/wt genotype, the presence of either I/I249 or M/M280 genotypes increased the risk for impaired cognition, suggesting that genetic variants resulting in less available CX₃CR1 may increase the risk for impairment of the central nervous system in HIV-infected children².

Conclusion
These and several other genetic factors (to be discussed in part 2 of this publication) involved in the regulation of HIV-1 infection have served to improve our understanding of the molecular basis of retroviral infection, bringing the scientific community closer to the development of effective vaccines or therapies.

References

1. Piacentini L, et al. 2008. Genetic correlates of protection against HIV infection: the ally within. Journal of Internal Medicine 256:110-124.

2. Singh KK and Spector SA. 2009. Host genetic determinants of HIV infection and disease progression in children. Pediatr Res. 2009 Jan 28 [Epub ahead of print] Doi:10.1203/PDR.0b013e31819dca03

Natural immunity against HIV: will it offer solutions? (Part 2)

Introduction
The race to finding some form of protection against HIV or AIDS is still on, and the natural immunity against HIV or progression to AIDS seen in a handful of people exposed to the virus has proven to be very valuable to improve our understanding of the infectious mechanisms of the virus. In part one of the series, the focus was on mutations in, or associated with, the genes of chemokine receptors, mannose binding lectin, human leukocyte antigens (HLA). Some other genes, as well as a recent protein study was briefly touched on. In part two, TRIM5α and APOBEC3G will be discussed in some detail.

TRIM5α
TRIM5α is a host endocellular protein belonging to the tripartite motif family and is believed to restrict HIV replication within the host cell by binding to the viral capsid. The protein also inhibits virus production by accelerating degradation of the viral Gag protein^1,2. Genetic studies seem to be controversial. In humans, the wild-type form of the TRIM5α gene offers little resistance against HIV-1. However, it was found that the R136Q polymorphism in TRIM5α is associated with resistance to HIV infection. Curiously, the 136Q allele was found more frequently in HIV-infected individuals compared to exposed seronegative (ESN) individuals in a Caucasian population, whereas in an African American population, 136Q was more frequently seen in ESN, compared to HIV-infected individuals. There are indications that co-presence of 136Q and -2GG alleles (in the 5’ untranslated region of TRIM5α) may predispose a patient to accelerated disease progression. Furthermore, the 43Y allele was associated with ESN in vivo, as opposed to a higher susceptibility to HIV infection in vitro¹.

APOBEC3G
Another host endocellular protein, APOBEC3G (Apolipoprotein B mRNA Editing Catalytic Polypeptide 3G), contributes to resistance to HIV infection. APOBEC3G is incorporated into virus particles, causing hypermutation and consequently premature degradation of viral cDNA. However, APOBEC3G is effectively neutralised by the virus through a protein called virion infectivity factor (Vif) which mediates polyubiquitination and degradation of the host protein^1,3. Genetic variants of the APOBEC3G gene exist that modify the rate of disease progression to AIDS. H186R, which is more prevalent in African Americans than American Caucasians (37% vs. 3%), is strongly associated with more rapid decline of CD4+ cells and thus accelerated progression to AIDS. Similarly, the allele C40693T is associated with increased risk of infection in ESN, as well as more rapid disease progression in infected individuals. In contrast, an F119F variant is associated with moderate decrease in rate of disease progression^1,2,3.

There are indications from in vitro experiments that the level of expression of wild type APOBEC3G may alter the course of HIV infection. It has been shown that even slight changes in expression of the protein result in decreased viral replication. Higher basal and IFNα-stimulated APOBEC3G mRNA and protein levels were seen in ESN in a study comparing ESN to HIV-infected and healthy individuals. This may be attributed to the fact that ESN would respond to IFNα with faster and more robust production of APOBEC3G. No effective mutations have been detected in the APOBEC3G promoter, indicating that varying expression of the protein is likely due to immune modulation by cytokines such as IFNα¹. This implies that polymorphisms in external regulatory elements of APOBEC3G may play a role in resistance to HIV-1.

Conclusion
It is clear that no one host factor can account for the resistance against HIV-1 that is seen, and accordingly, no one factor will cure AIDS. Rather, an accumulation of information on the different mechanisms employed by the human body to neutralise HIV-1 may lead to a concerted effort to develop a vaccine or treatment that employs a battery of elements in combination. Such a vaccine or treatment may ultimately need to take into account the genetic makeup of an individual.

References

1. Piacentini L, et al. 2008. Genetic correlates of protection against HIV infection: the ally within. Journal of Internal Medicine 256:110-124.

2. Takeuchi H and Matano T. 2008. Host factors involved in resistance to retroviral infection. Microbiol Immunol. 52:318-325.

3. Singh KK and Spector SA. 2009. Host genetic determinants of HIV infection and disease progression in children. Pediatr Res. 2009 Jan 28 [Epub ahead of print] Doi:10.1203/PDR.0b013e31819dca03

Author: Marisa Tait
Reviewed by: Hendra van Zyl
Contact: afroaidsinfo@mrc.ac.za
Date: April 2009

Last updated: April 2009

HIV Becoming More Virulent. 08/04/09

Wednesday, April 08, 2009

Health 24

Damage to patients’ immune systems is happening sooner now than it did at the beginning of the HIV epidemic, suggesting that the virus has become more virulent, researchers report. 

Conventional wisdom says several years will pass between HIV infection and the need for antiretroviral therapy. However, clinicians have observed that patients are entering HIV care with lower initial CD4 cell counts than in previous years, and now often require antiretroviral therapy soon after entering care, raising the question of whether HIV has become more virulent. 

US researchers studied data from more than 2 000 HIV-positive active-duty military personnel, retirees, and dependents between 1985 and 2007 who had tested HIV-negative within the previous four years. 

When they looked at patients’ first CD4 count after HIV diagnosis, they found that it decreased from an average of 632 cells per square millimetre in 1985-1990 to 514 in 2002-2007. 

Additionally, 25% of patients diagnosed with HIV in recent years already had fewer than 350 CD4 cells per square millimetre, the threshold for when antiretroviral therapy should begin according to US guidelines, compared to only 12 percent of patients in the late 1980s. 

Trend stabilising

The authors note that the trend seems to have stabilised, perhaps due to the widespread introduction of highly active combination antiretroviral therapy. 

This is the first study from the United States which shows that the immune cells among recently diagnosed HIV patients has dramatically fallen during the HIV epidemic, the authors said in an official statement. These findings are similar to those found in a study from Europe, which suggests that these trends may be widespread. 

“Unfortunately, it may no longer be true that there is a time period of several years between diagnosis and the need for treatment – instead this time-span is shortening” said study author Dr Nancy Crum-Cianflone, of the San Diego Naval Medical Centre. “Early diagnosis is important for several reasons including that patients can enter into medical care and begin treatment before the immune system becomes weak and opportunistic infections develop.” 

The study is published in the May 1, 2009 issue of Clinical Infectious Diseases. – (EurekAlert, April 2009)

Reducing TB a Matter of Life and Death. 01/04/09

DURBAN, 1 April (PLUSNEWS) - Several years ago, the World Health Organization (WHO) identified the three most important ways of reducing the risk of tuberculosis (TB) in people living with HIV, who are highly susceptible to the airborne disease.

The approach was widely recognized as effective and feasible, and incorporated into a number of national TB policies, yet TB - the most common and life-threatening opportunistic infection in people living with HIV - claimed the lives of an estimated 230,000 HIV-positive people in 2008, according to WHO.

South Africa, which accounts for a third of all patients co-infected with HIV and TB in Africa, is among the countries that adopted the 3 I's, but presentations to a symposium on 31 March at the 4th South African AIDS Conference in the east-coast city of Durban, said implementation had been virtually non-existent.

"Let's just do it!" several speakers urged in an effort to galvanize the support of attendees, many of whom work in the health sector, to translate TB reduction policies into action.

Trying to slow the spread

Studies have found that a lack of infection control - the first "I", and perhaps the most fundamental in preventing new TB cases - was largely responsible for the outbreak of extensively drug-resistant TB (XDR-TB) in South Africa's KwaZulu-Natal Province in 2006.

Lesley Odendal, an infection control coordinator with Médecins Sans Frontières, the international medical humanitarian organization, said the majority of drug-resistant TB cases in South Africa were the result of primary infection rather than patients not adhering to first-line TB drugs - "the clearest illustration we're failing in infection control".

Basic interventions, such as ensuring an adequate supply of masks to healthcare workers and patients, educating communities about how to reduce the spread of TB, and supporting individual healthcare facilities to design their own infection control plans, were lacking. "These are simple measures and it's despicable that we aren't implementing them."

Odendal also noted that a national infection control policy had been in draft form since 2007.

Catching cases early

The second "I"', intensified case finding, means regularly screening people infected with HIV, and other groups at high risk of TB, such as healthcare workers and miners, rather than waiting for patients to present with symptoms.

"Passive case-finding is not effective," said Dr Celine Gounder of Johns Hopkins University, in Baltimore, in the US. "By the time a patient is symptomatic they're infecting others, and mortality rates are high."

Gounder cited a Cape Town study which found that only about one-third of HIV-positive patients with TB were diagnosed.

Dr Salome Charalambous of the Aurum Institute, a health research NGO, noted that HIV-positive patients were usually only screened for TB before starting antiretroviral (ARV) treatment, but remained at a higher risk of TB even after starting anti-AIDS medication. "There needs to be continuous screening," she said.

Sputum tests, the quickest and cheapest TB screening method, are less effective in HIV-positive patients and have to be combined with other approaches, such as chest x-rays and symptom check-lists, but a study in 24 communities in South Africa and Zambia has shown that TB case detection can be dramatically increased by educating communities about the benefits of regular TB screening and ensuring easy access to it.

Using available methods

Providing Isoniazid Preventive Therapy (IPT) to people living with HIV, the final "I", can lower their risk of contracting TB by 33 percent, but in 2008 less than 7,000 HIV-positive people in South Africa received a six-month course of the drug.

With the exception of Botswana, other countries are not doing much better. According to the latest global TB control report by WHO, only about 29,000 people were started on IPT worldwide in 2007. Rolling out IPT depends on improved TB screening, as patients can only be given this treatment if they do not have active TB.

WHO also recommends TB skin tests, which can determine whether a patient has latent TB infection, but speakers at the symposium were in favour of removing this requirement from South Africa's guidelines, as the tests are widely considered to be unreliable and a further barrier to making IPT widely available.

Concerns about adherence, drug resistance, the difficulty of ruling out active TB, and the cost of IPT have all been given as reasons for not providing it, but Dr Vincent Tihon, a TB-HIV advisor to South Africa's department of health, dismissed these as excuses.

He said there was no evidence that IPT promoted drug-resistance, and the intervention was much cheaper than treating TB; political commitment to roll out IPT more widely in South Africa had increased in recent months and revised IPT guidelines were expected to be approved by June.

"IPT is feasible and cost-effective," said Prof Harry Hausler of the University of Western Cape. "Failure to provide [it] is a human rights violation and will worsen the epidemic; let's just do it."

© IRIN. All rights reserved. HIV/AIDS news and analysis: http://www.plusnews.org/

4th SA AIDS Conference. 06/05/09

 You can find material about the faith involvement at the conference here.

To Stop A Killer. 31/03/09

Lesley Odendaal

Mar 31 2009

Only 4% of South Africans living with HIV in South Africa are receiving preventative therapy for tuberculosis and only 1% are being screened for TB.

This is despite the fact that TB remains the leading cause of death in South Africa and that deaths from the disease have tripled in the past 10 years.

HIV infection is a key factor in the growing incidence of this curable disease. In some communities the HIV and TB co-infection rate is as high as 85%, while at least half of HIV-infected people in South Africa also have TBand vice versa.

These are shocking statistics in a country where political leaders constantly claim to be doing their utmost to protect the health of the populace.

Health activists have achieved great success in mobilising against Aids denialism and pressuring for effective government policy. Why, then, are we not screaming from the rooftops about TB and TB-HIV co-infection and implementing novel approaches to offset the dire public health consequences?

The silence is deafening.

Of particular concern is drug-resistant TB, where in some settings HIV co-infection is also at about 75%. This cannot be treated with the strongest TB drugs and the cost of treating it with special medication can be up to 100 times higher than when using the standard drug treatment.

Drug-resistant TB can develop when TB patients fail to complete their full regimen of treatment. Such patients can infect thousands of others with the same drug-resistant pathogen. Far more people in South Africa catch drug-resistant TB in this way than by not completing treatment.

The recorded number of multidrug-resistant (MDR) TB cases has grown from about 3500 in 2004 to almost 10000 patients. Even more deadly is extensively drug-resistant TB (XDR), which has increased from 74 to 535 cases in the same period.

The lack of capacity and infrastructure for diagnosing and treating MDR and XDR-TB and the high death rates associated with these strains of tuberculosis, combined with the effect of HIV co-infection, means that this has become one of the direst health emergencies facing South Africa today.

It is only relatively recently -- after hype in international circles surrounding drug resistance -- that there has been some movement towards confronting the crisis.

There have been some good results with regard to drug development, proving that with the necessary resources new treatments and diagnostics are possible.

But the real challenge does not lie in the range of drugs South Africa has at its disposal -- it is about how it gets these drugs to the people and about how it diagnoses the disease in the first place.

Barbara Hogan may be a dedicated and efficient health minister, but that doesn't change the fact our health system has been badly eroded. Our primary healthcare approach is failing, with people regularly arriving at hospitals close to death.

NGOs, researchers, clinicians, activists and patients must collectively focus on this tragedy.

World TB Day passed on Tuesday and the chances are that very few of our citizens were aware of it -- despite the fact that scores of South Africans will have died of TB on that very day.

This week HIV clinicians, researchers, activists and students will come together at the fourth South African Aids conference in Durban.

Important though they may be, South Africa should not focus on the latest scientific developments and engage in congratulatory back-slapping of leading scientists for new discoveries.

The centre of our endeavour should be about how we plan to implement the science to revolutionise our public health system to prevent thousands of unnecessary deaths.

Lesley Odendal is a member of the Treatment Action Campaign

HIV Transfer Caught on Video. 30/3/09

The transfer of HIV from infected to uninfected immune system T-cells has been captured on video for the first time, in an achievement that could lead to new ways to block the transmission of HIV, researchers say.

"Most prior studies of HIV dissemination have focused on free-roaming viruses, but this study shows us how direct T-cell-to-T-cell contact could, in fact, be the predominant mode of dissemination within the body," said Dr Benjamin Chen, an assistant professor of medicine and infectious diseases at Mount Sinai School of Medicine in New York City.

The team of researchers from Mount Sinai and the University of California, Davis, Center for Biophotonics Science and Technology, discovered that HIV moves between T-cells through structures called virological synapses.

"Direct T-cell-to-T-cell transfer through virological synapses is a highly efficient avenue of HIV infection. Our recent experiments show that the viral structural protein moves with surprising speed in infected cells, and that the cell machinery actively participates in the transport of virus between T-cells. This suggests there are many targets for interfering with the process," Chen said.

How they did it

To capture the transfer of HIV from T-cell to T-cell on video, the researchers created a molecular clone on infectious HIV that contained a green fluorescent jellyfish protein. Quantitative, high-speed, 3D video microscopy was used to record both viral particle formation and HIV transmission between T-cells.

"We found that the transfer of HIV is highly co-ordinated between T-cells, and that the transfer is rapid and massive. Future efforts to block HIV transmission may be designed to specifically exploit and block this cell-to-cell mode of infection," Chen said.

The study appears in the March 27 issue of Science. – (HealthDay News, March 2009)

New Insight into HI-Virus. 27/02/09

New research has revealed the extent and speed at which the HI virus can adapt to overcome the body's own evolving defence systems. 

In an international study, published on Wednesday in the scientific journal, Nature, researchers looked at HIV genetic sequences in over 2,800 people in six different countries in Europe, North America, the Caribbean, Asia and sub-Saharan Africa to determine how the virus had evolved to respond to a key set of molecules in the human immune system called human leukocyte antigens (HLAs).

The type of HLA genes an individual has can determine their ability to fight HIV infection, which partly explains why some people can live with the virus for more than 20 years without treatment while others progress to AIDS within a year.

Researchers have determined that certain HLA genes that are effective at controlling HIV are more prevalent in some populations than others. But the study also found that in these populations, mutations in the HI virus - enabling it to counteract the protective effect of these genes - were also more common.

The findings help explain why different strains of HIV have developed in different parts of the world. In countries with high rates of HIV infection, strains carrying what the researchers called 'escape mutations' have been able to replicate more rapidly than in countries with low infection rates.

"The effect we're describing is far more likely to be seen in the very places where we're trying to make vaccines," said lead researcher Prof Philip Goulder of Oxford University in the UK.

Scientists have long known that the HI virus can mutate rapidly in an individual, but the study provides evidence that mutations in the virus can also spread in a population, posing immense challenges to vaccine development.

If or when researchers are successful in developing an effective vaccine, the study findings suggest that it will have to be modified frequently to keep up with new mutations in the virus.

However, the findings are not a reason to give up hope. "It doesn't necessarily mean the virus is winning, just that the ground is shifting. It may be less virulent in the future - we just don't know," Goulder insisted.

"In spite of the fact that we haven't got a vaccine yet, and there have been major setbacks, there's also been major progress," he told IRIN/PlusNews.

New AIDS Approach Disrupts Patient's DNA. 13/02/09

WASHINGTON (Reuters) - California biotechnology company Sangamo BioSciences Inc. said on Monday it will start human testing of a new approach to treating the AIDS virus that involves deliberately damaging the patient's DNA.

The approach is based on research that has long shown that people with a certain mutation in a gene called CCR5 resist infection with the fatal and incurable virus.

The gene controls a doorway called a receptor in immune system cells. The human immunodeficiency virus uses the CCR5 receptor to latch onto the cells it infects.

Sangamo's drug SB-728-T disrupts CCR5. It is a zinc finger nuclease -- a compound that can slice open molecules.

This one is specifically designed to disrupt CCR5. The company plans to remove immune cells called CD4 T-cells from HIV patients, treat them with the drug and re-infuse them.

The hope is these damaged cells will thrive and multiply and give the patient an immune system resistant to HIV.

"This is the first time that we have had the ability to make a patient's T-cells permanently resistant to infection by CCR5-specific strains of HIV and we are very excited to begin a clinical trial of this novel zinc finger nuclease-based therapy," said Dr. Carl June of the University of Pennsylvania School of Medicine, who will help test patients.

The company said its phase I study is meant to look for safety only, and 12 patients with advanced HIV infection will be recruited.

"The ability to protect immune cells from infection with HIV and the expansion of CCR5-modified T-cells has the potential to provide long-term control of both the virus itself and eventually the opportunistic infections characteristic of AIDS," June said.

In November, German researchers reported that a bone marrow transplant to replace the immune system of an HIV patient with leukemia not only treated his cancer, but appeared to have suppressed the AIDS virus as well. The transplant was from a donor who had the CCR5 mutation.

(Reporting by Maggie Fox; Editing by Sandra Maler)

Evolving DNA Boost HIV Survival. 02/03/09

Researchers from the University of Alabama at Birmingham and the University of Oxford say any successful AIDS vaccine must keep pace with the ever-changing immunological profile of the human immunodeficiency virus. The scientists who analyzed genetic data from more than 2,800 HIV-infected patients on five continents described HIV's ability to adapt by detailing at least 14 different "escape mutations" that help keep the virus alive after it interacts genetically with immunity molecules. 

"Key genetic regions of HIV introduced into individuals of different ancestry in different places have been evolving to a greater or lesser degree according to inherited factors controlling immune response," said Dr. Richard Kaslow, a University of Alabama at Birmingham professor. "If HIV adapts differently in genetically distinct hosts, the challenge ahead in vaccine design is formidable." 

The study, which included scientists from Japan, Australia, Spain, Barbados, Botswana, South Africa and Canada, appears in the online issue of the journal Nature.

A First Step Toward a Cure for AIDS? Novel Procedure Appears to Have Eliminated HIV. 05/11/2008

By Jeffrey Laurence, M.D.

amfAR

November 5, 2008—We need a cure for AIDS. We can’t treat our way out of this epidemic. Anti-HIV therapy is a lifelong commitment, accompanied by many life-altering and some potentially life-threatening side effects. And for every person placed on treatment, two to three are newly infected. In 2007 alone there were 2.7 million new infections, and only 31 percent of those who needed treatment received it. Viral reservoirs—cells and tissues in which HIV remains dormant, beyond the reach of anti-HIV drugs but poised to grow at any moment—persist for the life of an infected person. And while all currently available anti-HIV drugs suppress the virus, they cannot eliminate it.

Given this context, a brief report in February 2008 by a group of physicians from Germany appeared to change everything when presented as a poster at the annual Conference on Retroviruses and Opportunistic Infections in Boston. It described a 40-year-old man—an American working in Berlin—whose HIV had been under good control for several years using a typical cocktail of drugs known as HAART. Then he developed acute leukemia.

In an attempt to cure the leukemia, he underwent a course of radiation therapy and chemotherapy in preparation for a stem cell transplant. But in his case, rather than simply using the best match among available stem cell donors, his physicians did something very clever. They also screened potential donors for a natural mutation known as delta32 CCR5. CCR5 is the primary means by which most types of HIV infect cells. Individuals lacking this CCR5 receptor—the 1.5 percent of the Caucasian population in America and Europe with the delta32 mutation—are completely resistant to infection by the most common forms of HIV.

The patient’s stem cell transplant was a success, although relapse of his leukemia required a second transplant using the same donor. Now off all anti-HIV drugs for almost two years, the patient continues to show no detectable signs of HIV in his blood, bone marrow, lymph nodes, intestines, or brain. To the limits of our ability to detect HIV, it appears that the virus has been eradicated from his body. At the very least this patient represents a functional cure: he is off all anti-HIV meds, has a normal T-cell count, and exhibits no evidence of virus.

amfAR quickly called together 10 experts in clinical AIDS, stem cell transplantation, and HIV virology for a two-day think tank at the MIT Endicott House to evaluate these data. The patient’s physician, Gero Hutter, presented details of the case, which were closely scrutinized by all. In a summary statement, attendees indicated that this case does indeed represent at least a functional cure. Dr. Hutter agreed to ask his patient to provide additional blood samples so that scientists attending the amfAR meeting could perform even more sensitive tests to attempt to further document that the virus has been erased from the patient. amfAR is coordinating distribution of these samples.

But amfAR’s involvement doesn’t end there. It is possible that the patient may have been cured of HIV/AIDS. But the cost of such a stem-cell transplant procedure can run up to $250,000. It is associated with a relatively high death rate from infectious and immunologic complications, and the number of delta32-CCR5 donors of appropriate tissue type would be very small. Here further research may yield key answers.

For example, it is unknown whether the use of a delta32-CCR5 donor is essential. Perhaps the transplant procedure itself was the most important element. The potential to genetically engineer stem cells to remove CCR5 from a patient’s own stem cells also exists, and strategies to do so were discussed at the think tank. These and related issues will serve as topics for an upcoming amfAR grant cycle.

HIV Much 'Older' than Thought. 02/11/08

New research might cause researchers and scientist to re-think the HIV timeline.

See news reports below:

XVII International AIDS Conference. 06/08/08

The XVII International AIDS Conference and Ecumenical Pre-Conference was held in Mexico from 3-8 August 2008.

- News from the Ecumenical Pre-Conference and also other reports with a strong Christian or faith based focus is available here.

- News from the main XVII International AIDS Conference below.

Gene Variant May Increase HIV Risk. 17/07/08

By Will Dunham

Washington - A gene variant that emerged thousands of years ago to protect Africans from malaria may raise their vulnerability to HIV infection but help them live longer once infected, researchers said on Wednesday.

The findings could help explain why Aids has hit Africa harder than all other parts of the world.

People with the version of the gene have a 40 percent higher risk of becoming infected with the human immunodeficiency virus, or HIV, researchers in the United States and Britain wrote in the journal Cell Host & Microbe.

In Africa, the gene variant may account for 11 percent of HIV infections, the researchers said.

Sexual behaviour and other social factors cannot completely explain why more than two-thirds of the world's 33 million people infected with HIV live in sub-Saharan Africa, the researchers said. So genes may be playing a pivotal role.

The gene in question controls a protein on the surface of red blood cells.

But even as it elevates a person's susceptibility to HIV infection, having this version of the gene seems to slow the progression of Aids. Those with the variant who have been infected with HIV live roughly two years longer than people who do not have it, the researchers said.

Having the variant has become "a double-edged sword", said researcher Sunil Ahuja of the University of Texas Health Science Centre at San Antonio.

About 90 percent of people in sub-Saharan Africa have this gene variant, and about 60 percent of Americans of African descent also possess it, according to the researchers.

Of the 2.1-million people who died of Aids worldwide last year, 1.6-million were from sub-Saharan Africa, according to the United Nations.

The protein linked to the gene is called Duffy Antigen Receptor for Chemokines, or DARC. People with the variant do not have this particular receptor - a type of molecular doorway into cells - on their red blood cells.

People lacking the receptor are protected against infection by a malaria parasite known as Plasmodium vivax. This parasite is not the one responsible for the multitudes of malaria deaths that now occur yearly in Africa, but is still seen in some parts of Asia and the Middle East.

The researchers believe the gene variant arose long ago, perhaps protecting people in Africa against a deadly strain of malaria that may have swept through populations.

"We're probably talking about tens of thousands of years ago," said Robin Weiss of University College London.

The researchers made their findings in black Americans, not in a population in Africa. They looked at 1 266 HIV-infected people in the US Air Force who were tracked since the 1980s, as well as 2 000 non-infected people.

They found the variant to be far more common among the US blacks infected with HIV than those not infected.

Only a small proportion of people not of African descent carry this genetic mutation, and it is just about absent in people of European descent, the researchers said.

4th IAS Conference. 27/07/07

 Lyn's Comment: As usual with the large international conferences, a large amount of interesting reports and documents will result from the 4th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment and Prevention.

I will highlight key news reports, but if you are interested in the scientific reports, or would like more information, I suggest that you visit the Aidsmap website .

Expert commentary, capsule summaries of conference presentations and downloadable slide sets will be available soon from the Clinical Care Options HIV website.

Webcasts of many conference sessions are available rapidly after sessions take place at the K

HIV and Chimpanzees? May 2007

In the last couple of months, the debate about the origins of the HI-virus were rekindled by the publishing of reports of a study by Dr Paul Sharpe and other researchers from the University of Alabama-Birmingham, from the University of Montpellier and the University of Nottingham.

Medpage first reported from the CROI conference in February “CROI: Origins of HIV Traced to Chimps in Cameroon” “After a 15-year quest, scientists believe that they have finally tracked the origins of HIV to a troop of chimpanzees living in a remote corner of Cameroon, near the border of Gabon and the Congo Republic, in West Central Africa” Read the full article.

The New York Times said “Chimp Virus Is Linked to H.I.V”. “By studying chimpanzee droppings in remote African jungles, scientists reported yesterday, they have found direct evidence of a missing link between a chimpanzee virus and the one that causes human AIDS.” Read the full article.

The Kaiser Daily HIV/AIDS Report said “Scientists Confirm That HIV Originated in Wild Chimpanzees, Study Says” “Scientists on Thursday in a study published in the online edition of the journal Science confirmed that HIV originated in wild chimpanzees and likely crossed over into humans in Cameroon, the New York Times reports (Altman, New York Times, 5/26). Scientists for many years believed that HIV evolved from a similar virus called simian immunodeficiency virus that is found in chimpanzees, but until now that virus had been found only in chimpanzees in captivity (Xinhuanet, 5/26).” Read the article. 

In South Africa, the Mail and Guardian Online reported “Scientists trace origin of HIV to Cameroon”. The article begins “Scientists searching for the origin of HIV, the global pandemic infecting more than 40-million people, believe they have finally tracked its original source to two colonies of chimpanzees in a corner of Cameroon”. Read the article. 

The scientific article to which most of these reports refer,as well as some comments are available from Haart4Africa. 

As is usual in scientific debate, other scientists were quick to comment on this research, and in some cases, to differ from the findings. Edward Hooper, a proponent of the "oral polio vaccine" theory, said "Much of this new information is important and valuable. However, much of the accompanying analysis is exaggerated, and not for the first time seems to be driven by an underlying desire on the part of the authors to bolster the bushmeat theory…". You can read his opinion.

How should non-scientists respond to these differing opinions?

When one really thinks about it, arguments about the origins of the virus add very little to general prevention and care efforts. The origin of HIV is really only important to researchers who hope to use this research in understanding more about the virus and finding ways of treating those living with the virus and preventing infection.

If you follow the debate as a matter of interest, it can do no harm. Arguments about the origin of the virus can however draw attention away from the challenges facing us all.

In the CABSA Channels of Hope workshop, the following example is often used:

Imagine that you enter a room and see your child faced by a dangerous snake. What would your response be?

1. Would you start wondering where the snake came from (wonder about the ‘origin’ of the danger), or
2. Would you react as quickly as possible to get your child out of harm’s way (deal with the reality of the situation)?

Let us not get caught up in arguments that cause us to loose sight of the needs around us!

How AIDS Got to the US. 30/10/07

Downloaded Tuesday, October 30, 2007

The HIV strain that started the US Aids epidemic and fuelled the global spread of the disease reached North America from Africa via Haiti, according to a study released Monday. 

"Haiti was HIV's stepping-stone when it left central Africa and started to move around the world," said Michael Worobey, assistant professor of evolutionary biology at the University of Arizona, Tucson, and senior author of the paper. 

A single immigrant

The deadly virus probably arrived on US shores in about 1969, more than a decade before the full-blown US Aids crisis of the 1980s, and may have been carried there by a single Haitian immigrant, according to the study. 

"Once the virus got to the US, then it just moved explosively around the world," Worobey said. 

The finding confirms longstanding suspicions among some scientists that the pathogen was imported from Haiti - the poorest nation in the western hemisphere, with a long history of migration to the United States. 

The timing suggests that it was more likely to have been a Haitian immigrant or immigrants rather than US sex tourists returning from Haiti, since it did not become a destination for them until the 1970s, Worobey said. 

Date pushed back

The research also pegs the beginning of the US Aids epidemic to the late 1960s rather than the mid 1970s as was previously assumed, and suggests that the disaster was brewing for a full 12 years before US public health authorities realised they had an epidemic on their hands. 

It wasn't until 1981 that the first US Aids cases were reported among homosexual men in Los Angeles by the US Centres for Disease Control and Prevention.

The strain of the virus that touched off the US epidemic subsequently spread to Canada, Europe, Australia and Japan. 

It was not clear previously how the virus got to the United States from central Africa, where it first surfaced in humans around 1930 after jumping species from chimpanzee to man. 

How the discovery was made

To solve the riddle, Worobey and a team of international researchers conducted genetic analyses of archived blood samples from early Aids patients who migrated from Haiti to the United States. 

They used these analyses to make genetic family trees for the virus, which they then compared to the genetic sequences of Aids patients from other countries.

Their calculations suggested there was a greater than 99 percent probability that the virus went from Africa to Haiti to the United States. 

The research ties in with other facts that pointed to Haiti as the missing link in the chain of transmission. 

Firstly, many Haitian professionals worked for a time in the Democratic Republic of Congo after it achieved independence from Belgium in 1960. It is one of several central African nations where the disease has been established since the 1930s. 

In the early days of the US outbreak, the rate of Aids infections among Haitians living in the United States was 27 times higher than that in the broader US population.

Worobey and his colleagues also concluded that the virus jumped from Haiti to Trinidad and Tobago, causing the predominantly heterosexual outbreak on those Caribbean islands. 

The Aids problems on Haiti and Trinidad and Tobago were therefore not necessarily started by North American sex tourists visiting the islands in the 1970s or 1980s, as some scientists had speculated. – (Sapa-AFP)

Patients on HIV Drugs Could Live To 70s. 25/07/08

AIDSMap News 

Michael Carter, Friday, July 25, 2008  

A large international study has provided evidence that people taking HIV treatment can now expect to live into their 60s and beyond. The study is published in the July 26^th edition of The Lancet, and showed that an individual starting successful HIV treatment aged 20 would be expected to live to be 63, and that a patient initiating an anti-HIV drugs regimen aged 35 could live to the age of 67. It also provided evidence of the dramatic and continued decline in the risk of death amongst people with HIV since effective HIV treatment became available.

What is more, the researchers found that starting treatment with a CD4 cell count above 200 cells/mm³ would mean that a person aged 20 could expect to live to be 70, and that a 35 year-old could survive into their 72^nd year.

Nevertheless, they still found that even in their most optimistic estimates, the life-expectancy of HIV-positive individuals was approximately ten years shorter than that of an HIV-negative individual. Furthermore injecting drug users and patients who started HIV treatment with lower CD4 cell counts had lower life-expectancies.

The author of an accompanying editorial calls these findings “exciting” and believes that they underline the importance of prompt diagnosis and treatment of HIV. He also suggests that the risk of death would be diminished and overall prognosis further improved by starting anti-HIV drugs with a CD4 cell count of 500 cells/mm³.

Almost immediately after multi-drug antiretroviral therapy became available in 1996, doctors observed dramatic reductions in rates of illness and death in HIV-positive patients treated with such drugs. A number of studies have shown that antiretroviral therapy has the potential to dramatically improve the prognosis of HIV-positive patients, but they have only considered patients in single cohorts or countries.

Therefore researchers from the Antiretroviral Cohort Collaboration which involves 14 large HIV cohort studies in Canada, Europe and the USA, looked at rates of mortality and the life-expectancy of over 43,000 patients who started HIV treatment for the first time between 1996 – 99, 2000 – 02 and 2002 – 05. They also looked at whether there were any patient characteristics which affected the risk of death or prognosis.

A total of 2056 (5%) patients died. The mortality rate fell from 16 deaths per 1000 person years between 1996- 99 to 10 per 1000 person years between 2002 – 05.

They also noted significant improvements in the prognosis for HIV-positive patients in the ten years of the study. Overall, a 20 year-old starting HIV treatment between 1996 and 2005 would be expected to live another 43 years. Between 1996 and 1999, they calculated that such a patient would live to be 56 years old, but in the period 2002 to 2005 this had improved to a little under 70 years.

There were also impressive improvements in the prognosis of 35 year-olds starting treatment, with an expectation of a further 32 years in life after HIV therapy was initiated. But, once more, prognosis improved over time from an expectation of a further 25 years of life in 1996 – 99, to 32 years by 2002- 05.

Patients who started HIV treatment with a low CD4 cell count (below 100 cells/mm³) had much higher mortality rates than patients initiating antiretroviral therapy with a CD4 cell count above 200 cells/mm³ (aged 20 – 44, 20 per 1000 person years vs. five per 1000 person years).

Furthermore a 20 year-old starting treatment with a CD4 cell count below 100 cells/mm³ would have a life-expectancy of 54 years compared to a life-expectancy of 70 years for a 20 year-old starting treatment with a CD4 cell count above 200 cells/mm³. The importance of CD4 cell count at the time of therapy initiation to prognosis was also seen in 35 year-olds, with patients with a CD4 cell count below 100 cells/mm³ expected to live until they were 62 compared to a prognosis of 72 years for patients with a CD4 cell count above 200 cells/mm³.

The investigators also found that women had a better prognosis than men, but that injecting drug users had a life-expectancy that was up to 20 years shorter than non-injecting drug users.

“There has been an improvement of outcomes with combination antiretroviral therapy between 1996 and 2005, characterised by a marked decrease in mortality rates” write the investigators. They attribute such reductions in mortality and improvements in life-expectancy to “improvements in therapy during the first decade of combination therapy.”

But they note that their study suggests that the prognosis of people taking antiretroviral therapy is still not normal. Picking up on this point, the author of the accompanying editorial highlights the findings of the SMART study which showed that patients with lower CD4 cell counts had a higher risk of serious non-HIV-related illnesses. The SMART study’s conclusions were one of the factors leading to HIV treatment guidelines recommending that antiretroviral therapy should be started at a CD4 cell count of 350 cells/mm³. The author notes the “clinical mischief of untreated HIV infection” and looks forward to the results of a clinical trial which could show if there is any benefit in starting HIV treatment at a CD4 cell count of 500 cells/mm³.

Reference

The Antiretroviral Cohort Collaboration. Life expectancy of individuals on combination therapy in high-income countries: a collaborative analysis of 14 cohort studies. The Lancet 372: 293 – 299, 2008.
Cooper DA. Life and death in the cART era. The Lancet 372: 266 – 267, 2008.

Where Research has Brought Us. 16/04/07

Belinda Beresford

Mail & Guardian Online

Two and a half decades of research have produced increasing returns in combating the HIV/Aids epidemic, with dramatic improvements in treatment and greater awareness of potential ways to stop the spread of the virus. What has not kept pace is the ability to get these medical interventions to people in need. No matter how powerful a drug or a procedure is, it is useless to those who cannot access it. The HIV/Aids pandemic has social and economic drivers that also need to be factored into interventions.

Circumcision

Barring the post-coital shower, male circumcision has been the hottest topic in HIV prevention in the past year or so. A study conducted in Orange Farm outside Johannesburg found that circumcising men reduced their chances of catching HIV by about two-thirds.

Further research in Uganda and Kenya confirmed the effectiveness of removing male foreskins, which contain high levels of cells preferentially targeted by HIV, and create a micro climate for this and other sexually transmitted infections. This month saw United Nations’ agencies urge countries with high HIV prevalence to offer male circumcision as part of a package of prevention strategies, including counselling to remind men and their partners that circumcision only offers partial protection.

A question hangs over the extent of behavioural disinhibition -- increase in sexually risky behaviour -- that might occur when men believe they are safer from HIV and whether it will outweigh the protective effects over time.

Although the procedure confers a significant degree of protection, there are potential problems. In particular, men who have sex before their wound has fully healed appear to be at higher risk of transmitting and contracting HIV.

Research is ongoing into the benefits and potential risks of male circumcision, both for the men and for their sexual partners. There is a vocal and sometimes highly emotive anti-male circumcision lobby that questions the ever-growing evidence of the benefits of the procedure.

Antiretroviral therapy

They don’t cure HIV, but antiretrovirals (ARVs) have become ever more successful at extending people’s lives. Recently a Danish study found that a 25-year-old starting ARV treatment has a life expectancy of 35 years. The development of new drugs is reducing side effects and the “pill burden” -- the number of pills that must be taken each day -- which makes it easier for people to adhere to therapy.

Until relatively recently there were just three classes of drugs and resistance to one often meant a degree of resistance to the whole group.

There is now a host of new ARVs in the pipeline, including many that affect the life cycle of the virus at different stages. This means they are not affected by any resistance to older medicines that may have developed.

The discovery that a genetic mutation renders some people virtually immune to HIV, because it prevents HIV from attaching to the CCR5 receptors on cell surfaces, has led to research into CCR5 inhibitors.

Delivery of paediatric ARV treatment has lagged behind, even though children often show dramatic responses to the drugs. In the United States about 98% of HIV-positive children are expected to live to adulthood, and to have life spans close to those of their uninfected peers. In some areas of Africa half of HIV-positive infants are expected to die before they turn two.

Fewer ARVs are registered for paediatric use, partially because of ethical concerns about conducting clinical trials on children. While there is a huge need for paediatric ARVs in developing countries, the market in developed countries is small because prevention measures mean that few infants are infected with HIV via their mothers.

Prevention of mother-to-child transmission

Mother-to-child transmission of HIV (MTCT) from pregnant and breastfeeding mothers to their infants has created a paediatric HIV epidemic. Worldwide it is thought that MTCT was the cause of most of the estimated 700 000 new HIV infections of children in 2005. But in developed countries MTCT has almost been eradicated by a combination of multiple ARV drugs, Caesarean deliveries and avoidance of breastfeeding.

Attention is now focusing on the merits and demerits of starting pregnant women on antiretroviral therapy (ART) earlier than non-pregnant women.

Research is also being done into potential benefits of offering short-term ART during pregnancy, and breastfeeding, to women who may be too healthy to need to start lifelong therapy. HIV transmission occurs through breastfeeding, but the alternative of formula feeding is often hazardous to infants because of the much greater risk of infection from inadequately sterilised equipment and water. Recent research from South Africa has confirmed that exclusive breastfeeding of children by HIV-positive mothers -- meaning the infant receives no other fluids or solids -- can reduce the chances of the child catching HIV and cut illness and death from other infant killers such as diarrhoea.

Tuberculosis

HIV/Aids has contributed to the spread of the active tuberculosis (TB) epidemic, which, in turn, has become the biggest opportunistic killer of people with HIV in South Africa. The continued spread of multi-drug resistant TB and the emergence of its more intractable derivative, extensively-drug resistant TB, is, in part, due to high levels of HIV/Aids. Most South Africans have latent TB, which activates when the immune system is sufficiently weakened. Inadequate diagnosis, treatment, facilities, and monitoring services mean that many people fail to successfully complete the initial six-month TB treatment, which can lead to drug resistance.

Although research is under way for better diagnostic tests, vaccines, and antibiotics against the bacillus, the cupboard is still relatively bare at a clinical level, compared with the amount of resources available against HIV.

As a result much work is being done on improving the use of existing technologies and medicines. In particular, healthcare workers are looking at improving the continuum of care between TB and HIV services so that people co-infected with the two pathogens are treated and monitored effectively and with minimum disruption to patients’ lives.

Vaccines

Much hope is pinned on the creation of vaccines that prevent the spread of HIV, but the appearance of a commercially available intervention is years away. A sign of the difficulty facing researchers, and the magnitude of the epidemic, is that a vaccine would be considered good enough for use if it were just 30% effective in preventing new infections.

Part of the problem is the length of time needed to run clinical trials to test the safety and efficacy of a vaccine. The vaccines being trialed now are based on knowledge of the virus and the immune system that existed several years ago. Current cutting-edge research is only going to be translated into large-scale human-efficacy trials years down the line.

The South African Aids Vaccine Initiative lists eight clinical trials in South Africa, including Phambili, the country’s first large-scale HIV vaccine test. The researchers hope the vaccine will trigger a sufficient immune response to wipe out potential HIV infections before they are able to settle into a new host. Alternatively, or additionally, the vaccine may be able to slow progression of HIV infection into Aids once people are infected.

Microbicides

Microbicides are a female-centred approach because of the power they could allow women over their reproductive health. Creating microbicides has proved more difficult than expected with two particularly severe setbacks.

Earlier this year a multinational clinical trial into the Ushercell microbicide, which included sites in South Africa, was stopped prematurely after it appeared that the anti-HIV gel may have increased the risk of infection among women. Researchers are still trying to understand these findings, because the gel had passed previous safety tests in humans.

Microbicides, which can take the form of gels, creams, films, sponges, or devices that release the active ingredients, are nicknamed “chemical condoms” because many were designed to create a physical barrier against HIV within the vagina. Later generation microbicides, such as vaginal rings that slowly release an antiretroviral, are designed to target the virus itself.