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