The ability of the human immunodeficiency virus (HIV) to escape immune surveillance in vivo is central to its pathogenicity and potentially limits our ability to develop effective vaccines. In HIV+ individuals, anti-HIV cytolytic T lymphocytes (CTLs) are clearly abundant and play a role in limiting viral loads, but they are unable to eradicate the virus. To better understand this enigma, we studied the efficacy with which anti-HIV CTLs are able to kill infected cells. This required the development of a unique system in which all infected cells could be identified (and quantitated) by the expression of placental alkaline phosphatase (FLAP). We used the PLAP marker to monitor the outcome of infected cells treated with CTLs. We found that HIV encodes at least one factor (nef) that protects infected cells from CTLs. Nef limited the ability of CTLs to kill infected cells by decreasing the density of MHC class I-epitope complexes on the surface of infected cells. In this proposal, we present experiments that will shed more light on the molecular mechanism of nef-mediated MHC class I downmodulation.