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Immune escape mutations in HIV-1 sequence: the influence of HLA class I and II alleles in a host population on viral evolution

Christiansen, F.T., John, M., James, I., Witt, C. and Mallal, S. (2002) Immune escape mutations in HIV-1 sequence: the influence of HLA class I and II alleles in a host population on viral evolution. In: 28th Annual Meeting of the American Society for Histocompatibility and Immunogenetics, 19 - 23 October 2002, Nashville, TN


The selection in vivo of mutations in HIV–1 that allow viral escape from host HLA class I restricted cytotoxic T cells (CTL) has been documented in idividuals. 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 CTL escape, CD4 T cell escape in HIV–1 was evident at a population level.

We analysed the diversity of HIV–1 RT sequences in 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 and polymorphism in HIV–1 RT in multivariate logistic regression models. Each single residue in HIV–1 RT (positions 20–227) was examined in separate models sequentially.

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 CTL epitopes, 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 (OR1, 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 CTL and CD4 T helper cell responses.

Item Type: Conference Paper
Murdoch Affiliation(s): Centre for Clinical Immunology and Biomedical Statistics
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