Traditionally natural killer (NK) cells are characterized as nonspecific effector cells, providing rapid recognition and lysis of virus-infected and neoplastic cells. However, recent work has shown that NK cells can demonstrate features of adaptive memory, including long-lived epigenetic modification intracellular γ-chain deficient (FcγR∆g) memory-like NK cells that require antibodies to grant antigen-specificity. Importantly, we have recently demonstrated for the first time evidence of antigen-specific NK cell memory in any primate species by characterizing HIV/SIV-specific NK cells in RM and showing an expansion of FcγR∆g NK cells in both HIV and SIV infections. Harnessing antibody mediated effector functions for HIV-1 vaccines will require a better understanding of effector cell biology, including the function and location (i.e. mucosal, systemic) of these newly identified memory-like NK cells and the interplay with FcR and Ig polymorphisms (with Project 1, 2). This Project will explore the specific hypothesis that polymorphisms in FcγRs (and Ig) in RM will modulate binding to memory natural killer cells and other effector cells thus influencing vaccine responses and subsequent protection against SHIV challenge. The specific aims for Project 3 are as follows: AIM 1: Determine FcγR expression and memory NK cell profiles in humans and RM. AIM 2: Determine functional differences between human and RM polymorphic FcγRs AIM 3: Perform a RM passive immunization study with defined FcγR genotypes/NK cell phenotype