ABSTRACT
BACKGROUND: HLA-B alleles of HIV-infected individuals have been shown to have a major impact on their rate of progression toward AIDS, and the T-cell responses they restrict are immunodominant. OBJECTIVE: We sought to identify whether the association of HLA-B alleles with rate of progression toward AIDS is due to targeting of more restricted and thus more conserved regions of the HIV-1 proteome. METHODS: Each residue of the HIV-1 consensus subtype B sequence was coded according to the presence/absence of an epitope, using the compiled epitope data available in the HIV-LANL immunology database. The Shannon entropy for each HXB2 position was calculated using pre-aligned HIV-1 clade B sequences as a measure of its degree of conservation. We then compared the entropy of empty versus epitope-containing positions and HLA-B-restricted versus HLA-A-restricted positions. RESULTS: Positions containing CD8 epitopes were significantly more conserved than corresponding empty positions. Moreover, residues targeted by HLA-B alleles in the HIV-1 proteome were significantly more conserved than the ones targeted by HLA-A alleles. Analysing a recent dataset, we found that B epitope regions contain significantly more escape mutations and reversions, which might be the reason why we find them to be more conserved. CONCLUSION: Our results suggest that epitopes in HIV-1 targeted by HLA-B alleles lie in more constrained regions of its proteins, in which mutations might have a higher fitness cost and tend to revert. Consequently, HLA-B-restricted cytotoxic T-lymphocyte (CTL) responses may persist longer. This may be one of the factors contributing to the immunodominance and impact of HLA-B-restricted CTL responses on disease progression.
