Abstract
The selection in vivo of mutations in HIV-1 that allow viral escape from host HLA class I restricted cytotoxic T lymphocyte (CTL) responses has been documented in individuals. Recently we showed that the many HLA-A and -B allele-specific polymorphisms in HIV-1 reverse transcriptase (RT) suggested extensive CTLescape mutation at a population level. HLA class II restricted CD4 T helper responses have a central role in HIV-1 immunity and associations between HLA class II alleles and HIV-1 disease progression have been reported. However, CD4 T cell escape mutation in HIV-1 has not been proven. We sought to determine whether, as for CTLescape, CD4 T cell escape in HIV-1 was evident at a population level as HLA-DRB1 associated polymorphisms.
We analysed the diversity of HIV-1 RT sequences in a large, well characterised cohort of HIV-1 infected patients over 2210 person-years of observation. We examined the relationship between the HLA-A, -B and -DRB1 alleles present in the cohort (as covariates) and polymorphism in HIV-1 RT (as the outcome) in multivariate logistic regression models. Each single residue in HIV-1 RT (positions 20-227) was examined in separate models sequentially. Power calculations and model selection steps were carried out to limit the number of comparisons, and final Bonferroni correction was made to mark out the most significant associations.
Polymorphism in HIV-1 RT occurred at sites with least functional constraint against mutation. At these sites, we identified 64 characteristic polymorphisms associated with specific HLA-A or -B alleles (OR > 1, p < 0.05). These polymorphisms were often within or proximate to known or putative CTLepitopes, and correlated with the known HLA allele restriction of these epitopes. There were also 13 polymorphisms that were independently associated with specific HLA-DRB1 alleles (OR > 1, p < 0.05). Four of the 5 known T helper cell epitopes in HIV-1 RT encompassed sites of HLA-DRB1 allele-specific polymorphism found in our study. There were also 'negative associations' between polymorphism and common HLA alleles, suggesting that the HIV-1 consensus sequence could have been selected by the host population's dominant HLA.
This novel, population-based approach shows that polymorphisms in HIV-1 sequence are characteristic for specific HLA class I and II alleles, in keeping with viral adaptation to both the CTLand CD4 T helper cell responses of a human host population. These findings suggest that HLA has a central role in HIV-1 primordial and contemporary evolution and has implications for epitope mapping and predicting HIV-1 dynamics in individuals.