CTL ontogeny and viral escape: implications for HIV-1 vaccine design

The protective role of CD8+ cytotoxic T lymphocytes (CTLs) in HIV-1 infection has prompted an emphasis on generating virus-specific CTLs by vaccination, whereas the determinants of antiviral efficiency remain undefined. The general strategy of many vaccines is to maximize the breadth of CTL responses. However, patterns of changing CTL specificity and viral mutation in natural infection, in addition to data from macaque and in vitro studies, suggest that a more focused approach might optimize the activity of vaccine-generated CTLs to prevent or attenuate infection. CTLs recognizing early proteins (Tat and Nef) appear to exert greater antiviral pressure but might be more prone to epitope escape mutation, whereas those recognizing structural proteins (Gag and Pol) might be more likely to persist through the recognition of conserved sequences. These principles could have important implications for vaccine design.