Unique Features of HLA-Mediated HIV Evolution in a Mexican Cohort: A Comparative Study

Background:Mounting evidence indicates that HLA-mediated HIV evolution follows highlystereotypic pathways that result in HLA-associated footprints in HIV at the population level.However, it is not known whether characteristic HLA frequency distributions in differentpopulations have resulted in additional unique footprints.Methods:The phylogenetic dependency network model was applied to assess HLA-mediatedevolution in datasets of HIV pol sequences from free plasma viruses and peripheral bloodmononuclear cell (PBMC)-integrated proviruses in an immunogenetically unique cohort of Mexicanindividuals. Our data were compared with data from the IHAC cohort, a large multi-center cohortof individuals from Canada, Australia and the USA.Results: Forty three different HLA-HIV codon associations representing 30 HLA-HIV codon pairswere observed in the Mexican cohort (q < 0.2). Strikingly, 23 (53%) of these associations differedfrom those observed in the well-powered IHAC cohort, strongly suggesting the existence of uniquecharacteristics in HLA-mediated HIV evolution in the Mexican cohort. Furthermore, 17 of the 23novel associations involved HLA alleles whose frequencies were not significantly different fromthose in IHAC, suggesting that their detection was not due to increased statistical power but todifferences in patterns of epitope targeting. Interestingly, the consensus differed in four positionsbetween 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 HLAmediatedselection in plasma viruses and PBMC archived proviruses at the population level, with asignificantly lower number of associations in the proviral dataset.Conclusion:Our data support universal HLA-mediated HIV evolution at the population level,resulting in detectable HLA-associated footprints in the circulating virus. However, it also stronglysuggests that unique genetic backgrounds in different HIV-infected populations may influence HIVevolution in a particular direction as particular HLA-HIV codon associations are determined byspecific HLA frequency distributions. Our analysis also suggests a dynamic HLA-associatedevolution 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 viruscompartment. These results highlight the importance of comparative HIV evolutionary studies inimmunologically different populations worldwide.