Virus-specific-CD8+ T cells play a central role in the control of viral infections by direct elimination of infected cells and secretion of a number of soluble factors. However, despite the induction of strong and broad HIV specific CD8+ T cell responses in chronic HIV-1 infection, these cells progressively lose critical effector functions. A number of recent studies have shown that a significant subset of CD8+ T cells appear to upregulate inhibitory "NK cell receptor" expression following encounter with antigen, and that CD8+ T cells expressing NK cell receptors persist in chronically infected mice but not in mice that clear the infection. These receptors included members of the KIR family, as well as of the C-type lectin family (NKG2) in humans and the Ly49 family in mice. The expression of these receptors on CD8+ T cells can have a profound effect on the functional capacity of both tumor-specific and virus-specific T cells. Recently, increased levels of KIR and NKG2A expression have also been described on discrete populations of CD8+ T cells in chronic HIV-1 infection. Given the profound inhibitory effect of these receptors, this application aims to gain a better understanding of the role of KIR and NKG2A receptor expression on HIV-1-specific CD8+ T cell function. In this application, the expression profile of both KIR and NKG2 receptors will be characterized on CD8+ T cells in subjects at different stages of HIV-1 infection to determine the kinetics of NK cell receptor upregulation in HIV-1 infection, to elucidate the impact of NK cell receptor expression on CD8+ T cell function, whether these receptors are preferentially enriched on the surface of HIV-specific CD8+ T cells, and whether this inhibitory effect can be reversed. Furthermore, the precise mechanisms accounting for NK cell receptor-mediated inhibition of CD8+ T cell activation will be characterized on the immunological synaptic level as well as the TCR signaling-cascade level. Thus this application aims to determine whether one of the mechanisms contributing to impaired CD8+ T cell activity during persistent viral infections may be due to an up-regulation of inhibitory NK cell receptors. These in depth studies geared towards understanding the underlying mechanism of KIR/NKG2A inhibitory activity on CD8+ T cells will certainly contribute to the field of basic CD8+ T cell biology and potentially allow for the identification of novel targets to reconstitute effective of CD8+ T cell immunity in the setting of chronic infections, such as HIV. [unreadable] [unreadable] [unreadable]