Natural killer (NK) cells are cytotoxic effector cells of the innate immune system that have been shown to play a central role in the control of viral infections, and increasing evidence suggests that NK cells also contribute to the control of HIV-1 infection. The presence of particular NK cell receptors, killer immunoglobuline-like receptors (KIRs) encoded in conjunction with their HLA class I ligands is associated with slower HIV-1 disease progression and better control of viremia, and NK cells expressing these protective KIRs have been shown to strongly inhibit HIV-1 replication in vitro. The goals of this proposal are to determine whether NK cells can mediate antiviral activity in HIV-1-infected individuals in vivo, and to identify the precise receptor/ligand interactions involved in the NK cell recognition of infected cells. The PI proposes to test the hypothesis that NK cells can impose significant immune pressure on HIV-1 in vivo, forcing the virus to evade NK cell mediated immune pressure by selecting for NK cell escape variants. If successful, these studies will establish NK cells as a new important effector cell population that, in concert with virus-specific CD8+ T cells and B cells, contributes to the control of HIV-1 replication in infected individuals and to HIV-1 diversity. These findings will have an important impact on the HIV-1 field by providing the rational to harness this arm of the antiviral immune response for HIV-1 vaccine design, in particular given the recent description in mice that NK cells can mediate immunological memory to viral infections.