HLA and AIDS: a cautionary tale

Intramural Research Support Program, SAIC Frederick, National Cancer Institute-Frederick, Frederick, MD 21702-1201, USA
Trends in Molecular Medicine (Impact Factor: 10.11). 10/2001; DOI: 10.1016/S1471-4914(01)02131-1
Source: PubMed

ABSTRACT The human major histocompatibility complex HLA has been implicated repeatedly as a regulator of the outcome of HIV exposure and infection. A new study of long-term survivors who naturally depress HIV-1 replication and avoid the signs of AIDS for years after infection suggests that homozygosity for a group of HLA-B locus alleles termed Bw4 confers resistance, ostensibly by regulating natural killer cell–ligand interactions. However, close inspection of the accumulated evidence raises some questions and urges validation of the potential Bw4 effects in additional studies.

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    ABSTRACT: Background The reproducible nature of HIV-1 escape from HLA-restricted CD8+ T-cell responses allows the identification of HLA-associated viral polymorphisms ¿at the population level¿ ¿ that is, via analysis of cross-sectional, linked HLA/HIV-1 genotypes by statistical association. However, elucidating their timing of selection traditionally requires detailed longitudinal studies, which are challenging to undertake on a large scale. We investigate whether the extent and relative timecourse of immune-driven HIV adaptation can be inferred via comparative cross-sectional analysis of independent early and chronic infection cohorts.ResultsSimilarly-powered datasets of linked HLA/HIV-1 genotypes from individuals with early (median¿<¿3 months) and chronic untreated HIV-1 subtype B infection, matched for size (N¿>¿200/dataset), HLA class I and HIV-1 Gag/Pol/Nef diversity, were established. These datasets were first used to define a list of 162 known HLA-associated polymorphisms detectable at the population level in cohorts of the present size and host/viral genetic composition. Of these 162 known HLA-associated polymorphisms, 15% (occurring at 14 Gag, Pol and Nef codons) were already detectable via statistical association in the early infection dataset at p¿¿¿0.01 (q¿<¿0.2) ¿ identifying them as the most consistently rapidly escaping sites in HIV-1. Among these were known rapidly-escaping sites (e.g. B*57-Gag-T242N) and others not previously appreciated to be reproducibly rapidly selected (e.g. A*31:01-associated adaptations at Gag codons 397, 401 and 403). Escape prevalence in early infection correlated strongly with first-year escape rates (Pearson¿s R¿=¿0.68, p¿=¿0.0001), supporting cross-sectional parameters as reliable indicators of longitudinally-derived measures. Comparative analysis of early and chronic datasets revealed that, on average, the prevalence of HLA-associated polymorphisms more than doubles between these two infection stages in persons harboring the relevant HLA (p¿<¿0.0001, consistent with frequent and reproducible escape), but remains relatively stable in persons lacking the HLA (p¿=¿0.15, consistent with slow reversion). Published HLA-specific Hazard Ratios for progression to AIDS correlated positively with average escape prevalence in early infection (Pearson¿s R¿=¿0.53, p¿=¿0.028), consistent with high early within-host HIV-1 adaptation (via rapid escape and/or frequent polymorphism transmission) as a correlate of progression.Conclusion Cross-sectional host/viral genotype datasets represent an underutilized resource to identify reproducible early pathways of HIV-1 adaptation and identify correlates of protective immunity.
    Retrovirology 08/2014; 11(1):64. · 4.77 Impact Factor
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    ABSTRACT: Some of the central challenges for developing effective vaccines against HIV and hepatitis C virus (HCV) are similar. Both infections are caused by small, highly mutable, rapidly replicating RNA viruses with the ability to establish long-term chronic pathogenic infection in human hosts. HIV has caused 60 million infections globally and HCV 180 million and both viruses may co-exist among certain populations by virtue of common blood-borne, sexual, or vertical transmission. Persistence of both pathogens is achieved by evasion of intrinsic, innate, and adaptive immune defenses but with some distinct mechanisms reflecting their differences in evolutionary history, replication characteristics, cell tropism, and visibility to mucosal versus systemic and hepatic immune responses. A potent and durable antibody and T cell response is a likely requirement of future HIV and HCV vaccines. Perhaps the single biggest difference between the two vaccine design challenges is that in HCV, a natural model of protective immunity can be found in those who resolve acute infection spontaneously. Such spontaneous resolvers exhibit durable and functional CD4(+) and CD8(+) T cell responses (Diepolder et al., 1995; Cooper et al., 1999; Thimme et al., 2001; Grakoui et al., 2003; Lauer et al., 2004; Schulze Zur Wiesch et al., 2012). However, frequent re-infection suggests partial or lack of protective immunity against heterologous HCV strains, possibly indicative of the degree of genetic diversity of circulating HCV genotypes and subtypes. There is no natural model of protective immunity in HIV, however, studies of "elite controllers," or individuals who have durably suppressed levels of plasma HIV RNA without antiretroviral therapy, has provided the strongest evidence for CD8(+) T cell responses in controlling viremia and limiting reservoir burden in established infection. Here we compare and contrast the specific mechanisms of immune evasion used by HIV and HCV, which subvert adaptive human leukocyte antigen (HLA)-restricted T cell immunity in natural infection, and the challenges these pose for designing effective preventative or therapeutic vaccines.
    Frontiers in Microbiology 10/2014; 5:514. · 3.94 Impact Factor


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