HLA-restricted immune responses have driven the evolution of HIV-1 clades
Park, L., Goulder, P., Kiepiela, P., Brander, C., Walker, B., Korber, B., Szinger, J., Keller, J., John, M., Nolan, D. and Mallal, S. (2005) HLA-restricted immune responses have driven the evolution of HIV-1 clades. In: 12th Conference on Retroviruses and Opportunistic Infections, 22 - 25 February 2005, Hynes Convention Center, Boston, MA.
Background. HIV mutates to escape selective pressure from antiretroviral medications and HLA-mediated immune responses. Escape mutations can, but do not necessarily, revert to “wild type” (WT) when the selective pressure is withdrawn. Worldwide, HIV has diversified into numerous clades and recombinant forms, and these variations generally follow geopolitical boundaries. Genetically similar human populations also follow these boundaries, so we hypothesized that population HLA has driven HIV evolution and its diversification into the clades.
Methods. HIV isolates from 2 HLA-typed cohorts of antiretroviral-naïve patients were analyzed; these isolates included 107 sequences from Caucasian patients in Australia infected with clade B, and 96 from patients in Durban, Africa, infected with clade C. Polymorphism rates were calculated for each amino acid residue in p24 and p17. Associations between HLA and each amino acid residue (comparing consensus vs all nonconsensus) were quantified using multiple logistic regression models with stepwise selection of HLA class I genotype as covariates. Consensus protein sequences for clades A, B, C, D, F, and G obtained from the Los Alamos HIV database were aligned and compared with the locations of polymorphism and HLA association.
Results. In p24 and p17, amino acid polymorphism (> 10% of the isolates differed from consensus) occurred at 50 and 56 residues in the Australian and African sequences, respectively. Of these, 33 were in common. Most of the alternative residues found in the Australian and African cohorts were the consensus amino acids for clades other than B and C, respectively. In each cohort, we found 38 residues with significant (p < 0.05) positive and/or negative associations between HLA and sequence polymorphism. The consensus protein sequences for clades A, B, C, D, F, and G differed at 79 residues. In both cohorts almost all of the polymorphic residues—42 (84%) for Australia and 46 (82%) for Africa—and HLA associations—32 (84%) for Australia and 30 (79%) for Africa—occurred at positions where the clade consensus sequences differed. These distributions were highly significant (Fisher p < 0.0001 for both).
Conclusions. After introduction of an HIV variant into a host, CTL-mediated immune pressure drives viral evolution within that host. At a population level we propose that the evolution of clades similarly reflects both founder effects and the selective pressures provided by the population HLA distribution.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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