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Abstract
BackgroundMounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level. However, it is not known whether characteristic HLA frequency distributions in different populations have resulted in additional unique footprints.MethodsThe phylogenetic dependency network model was applied to assess HLA-mediated evolution in datasets of HIV pol sequences from free plasma viruses and peripheral blood mononuclear cell (PBMC)-integrated proviruses in an immunogenetically unique cohort of Mexican individuals. Our data were compared with data from the IHAC cohort, a large multi-center cohort of individuals from Canada, Australia and the USA.ResultsForty three different HLA-HIV codon associations representing 30 HLA-HIV codon pairs were observed in the Mexican cohort (q < 0.2). Strikingly, 23 (53%) of these associations differed from those observed in the well-powered IHAC cohort, strongly suggesting the existence of unique characteristics in HLA-mediated HIV evolution in the Mexican cohort. Furthermore, 17 of the 23 novel associations involved HLA alleles whose frequencies were not significantly different from those in IHAC, suggesting that their detection was not due to increased statistical power but to differences in patterns of epitope targeting. Interestingly, the consensus differed in four positions between the two cohorts and three of these positions could be explained by HLA-associated selection. Additionally, different HLA-HIV codon associations were seen when comparing HLA-mediated selection in plasma viruses and PBMC archived proviruses at the population level, with a significantly lower number of associations in the proviral dataset.ConclusionOur data support universal HLA-mediated HIV evolution at the population level, resulting in detectable HLA-associated footprints in the circulating virus. However, it also strongly suggests that unique genetic backgrounds in different HIV-infected populations may influence HIV evolution in a particular direction as particular HLA-HIV codon associations are determined by specific HLA frequency distributions. Our analysis also suggests a dynamic HLA-associated evolution in HIV with fewer HLA-HIV codon associations observed in the proviral compartment, which is likely enriched in early archived HIV sequences, compared to the plasma virus compartment. These results highlight the importance of comparative HIV evolutionary studies in immunologically different populations worldwide.
Highlights
Mounting evidence indicates that human leukocyte antigen (HLA)-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level
Our data derived from analysis of HLAmediated HIV evolution in a previously uncharacterized, immunogenetically unique cohort from Central/Southern Mexico, support a highly conserved and strongly predictable component of HLA-mediated HIV evolution at the population level, resulting in HLA-associated footprints in the circulating virus worldwide
This effect is evident even after considering important objections to the HLAHIV population imprinting hypothesis, such as the rapid reversion of a considerable part of the total CD8+ T lymphocyte (CTL) escape mutations in the absence of the selective HLA allele [56], the complexity of the CTL response which frequently imposes conflicting selective forces in the same site of the viral sequence [27], the possibility that an escape variant selected by a specific HLA allele can be targeted by CTL responses restricted by different HLA alleles [18,30,57], and the dynamic immunodominance hierarchies observed in HLA-restricted responses [51,52]
Summary
Mounting evidence indicates that HLA-mediated HIV evolution follows highly stereotypic pathways that result in HLA-associated footprints in HIV at the population level. As a result of CTL-mediated selective pressure, immune escape mutations are selected that hinder viral peptide binding to HLA molecules, prevent peptide processing before their presentation or lower TCR affinity of specific CTL clones to peptide-HLA complexes [4,11,12,13]. Both the processes of antigen presentation to CTLs and CTL escape are HLA-restricted [14]
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