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

HIV-specific cytotoxic T lymphocytes (CTL) play a central role in the contr ol of HIV-I replication during primary infection. it has been hypothesized that the appearance of CTL escape mutants represents an important mechanism by which HIV-1 escapes the host cell-mediated immune response. However, ev idences for a direct relationship between CTL responses and emergence of CT L escape mutants are still limited. Here we report detailed longitudinal an alysis of DNA sequence variation performed over the entire HIV-1 envelope i n two subjects during primary HIV infection. Estimates of the frequencies o f synonymous (dS) and non-synonymous (dN) nucleotide substitutions were use d to identify regions of the HIV-1 envelope which were subjected to signifi cant levels of selective pressure. These regions were shown to comprise def ined epitopes recognized by CTL. Furthermore, dN mutation fixed within thes e epitopes effectively abolished recognition by the host CTL response. Thes e results provide compelling evidence that the CTL epitope mutations direct ly resulted from the selective pressure exerted by the virus-specific cytot oxic response.