Selective pressure exerted by immunodominant HIV-1-specific cytotoxic T lymphocyte responses during primary infection drives genetic variation restricted to the cognate epitope

National Center for Biotechnology Information, NIH, Bethesda, USAHIV-specific cytotoxic T lymphocytes (CTL) play a central role in the control of HIV-1 replica-tion during primary infection. It has been hypothesized that the appearance of CTL escapemutants represents an important mechanism by which HIV-1 escapes the host cell-mediated immune response. However, evidences for a direct relationship between CTLresponses and emergence of CTL escape mutants are still limited. Here we report detailedlongitudinal analysis of DNA sequence variation performed over the entire HIV-1 envelope intwo subjects during primary HIV infection. Estimates of the frequencies of synonymous (dS)and non-synonymous (dN) nucleotide substitutions were used to identify regions of the HIV-1 envelope which were subjected to significant levels of selective pressure. These regionswere shown to comprise defined epitopes recognized by CTL. Furthermore, dN mutationfixed within these epitopes effectively abolished recognition by the host CTL response.These results provide compelling evidence that the CTL epitope mutations directly resultedfrom the selective pressure exerted by the virus-specific cytotoxic response.