The role of mucosal resident virus-specific CD8+ T lymphocytes in acute SIV infection and the development of HIV vaccines

The success or failure of HIV vaccines may be linked to the fate of mucosal immune responses. Regardless of the route of infection mucosal tissues are active sites of virus replication and CD4+ T-lymphocyte depletion. During acute infection the development of virus-specific CD8 + T-lymphocyte responses only partially controls virus replication. We sought, therefore, to explore hypothetical explanations for this failure. In the SIV/rhesus macaque model of vaginal HIV transmission we examined key lymphoid tissues at two, three, or four weeks post-infection for development of virus-specific CD8+ T-lymphocytes. Despite robust responses at the site of infection, SIV-specific CD8+ responses appeared after the peak of virus replication. Concomitantly, we hypothesized that a vaccine inducing both mucosal and systemic virus-specific CD8+ T lymphocyte responses could control virus replication. We vaccinated six macaques with a DNA prime/recombinant Modified Vaccinia Ankara (rMVA) boost regimen encoding SIV proteins Tat, Rev, Nef, and the Mamu-A*01 minimal optimal epitopes Gag181-189CM9 and Tat28-35SL8. We induced strong CD8+ responses in peripheral blood mononuclear cells (PBMC), some expressing the mucosal homing and retention integrins alpha4beta7 and alphaEbeta7. Tetramer-binding cells were also detected in lymphocytes isolated from colon biopsies. The vaccinated animals, along with naive controls, entered two pathogenic SIVmac239 challenge regimens. Three animals received a single "high" dose of SIVmac239 (3000 TCID50; intrarectally (i.r.)) four months after their last rMVA boost and significantly reduced acute peak viremia. These animals, however, failed to control chronic infection. This may be due to the unnaturally large number of virions used to challenge, which may have overwhelmed an otherwise effective immune response. We, therefore, developed a more physiologically relevant challenge model. The remaining three vaccinees were challenged more than two years post-immunization with multiple "low" doses of SIVmac239 (30-300 TCID50; i.r.). The infected vaccinees, though, failed to significantly reduce virus replication in comparison to the controls. This vaccination suggests that mucosal CD8+ responses alone will be unable to control HIV replication. Yet given the importance of virus-specific CD8+ T lymphocytes in controlling acute virus replication it is still likely that inducing mucosal resident CD8 responses will be a key component of a successful HIV vaccine.