PROJECT SUMMARY (See instructions): Natural killer cells provide a critical early defense against viral pathogens by virtue of their ability to recognize and kill virus-infected cells without prior antigenic stimulation. This is accomplished through the integration of signals from killer-cell immunoglobulin-like receptors (KIRs) and C-type lectin receptors (NKG2A and NKG2C) on NK cells and their MHC class I ligands on target cells. KIR and HLA class I polymorphisms can have profound effect on the course of HIV-1 infection and the efficacy of NK cell-based therapies for eliminating virus-infected cells. However, animal studies to address the underlying immunological mechanisms have been hampered by our limited understanding of NK cell receptor interactions in nonhuman primate models. For MERIT extension of R37 AI095098 “KIR and MHC class I immunogenetics in SIV infection”, we will build on recent success defining the MHC class I ligands of rhesus macaque KIRs, isolating antibodies to these receptors, and investigating the effects of viral peptides on KIR-MHC class I interactions. We will also extend these studies to assess the influence of viral peptides bound by MHC-E on interactions with macaque NKG2A and NKG2C and to test the hypothesis that adaptive NKG2C+ NK cells have a significant impact on the course of SIV infection. Aim 1 will determine how KIR polymorphisms shape ligand recognition and generate reagents (antibodies and MHC class I tetramers) for differentiating these receptors on primary NK cells. Aim 2 will investigate the influence of viral peptides bound by MHC class I ligands on KIR and NKG2A/C interactions to address alternative hypotheses concerning the role of peptides in enabling NK cells to differentiate virus-infected cells from healthy cells or to facilitate immune evasion. Aim 3 will assess the contribution of adaptive NKG2C+ NK cells to the outcome of SIV infection by depleting these cells during the acute and chronic phases of SIV infection. This animal study will also afford an opportunity to investigate longitudinal changes in the phenotypic properties of NKG2A+ and NKG2C+ NK cell subsets in response to SIV infection using KIR-specific reagents generated in Aim 1.