HIV evolution: CTL escape mutation and reversion after transmission

Within-patient HIV evolution reflects the strong selection pressure driving viral escape from cytotoxic T-lymphocyte (CTL) recognition. Whether this intrapatient accumulation of escape mutations translates into HIV evolution at the population level has not been evaluated. We studied over 300 patients drawn from the B- and C-clade epidemics, focusing on human leukocyte antigen (HLA) alleles HLA-B57 and HLA-B5801, which are associated with long-term HIV control and are therefore likely to exert strong selection pressure on the virus. The CTL response dominating acute infection in HLA-B57/5801-positive subjects drove positive selection of an escape mutation that reverted to wild-type after transmission to HLA-B57/5801-negative individuals, suggesting that this CTL escape inflicts a significant cost to viral replicative capacity. A second escape mutation within the epitope, by contrast, was maintained after transmission. These data show that the process of accumulation of escape mutations within HIV is not inevitable. Complex epitope- and residue-specific selection forces, including CTL-mediated positive selection pressure and virus-mediated purifying selection, operate in tandem to shape HIV evolution at the population level.

A new mechanism of CTL escape has also been defined during the process of studying CTL-escape mutants in Gag p24. Mutations within CTL epitopes impair T-cell recognition, but escape mutations arising in regions flanking epitopes can also alter antigen processing. In HLA-B57+, HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the N-terminus of a dominant HLA-B57-restricted epitope. The A146P mutation prevented N-terminal trimming of the optimal epitope by the ER-aminopeptidase ERAP1. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance for selection of vaccine sequences.