The identification of a small subset of HIV-1 infected subjects that exhibit spontaneous control of viral replication (VL<75 copies RNA/mL) in the absence of anti-retroviral therapy (elite controllers) has heightened interest in the mechanism(s) of immune control over HIV-1. Originally, CD8 T cell responses directed against the HIV-1 Gag protein were found to be enriched in Elite controllers, as has been described previously for long-term non-progressors. However, approximately 40% of elite controllers within our associated cohort lack detectible HIV-1 specific Gag T cell responses suggesting that alternative mechanisms of immune control, such as innate immune effector responses, may also contribute to sustained viral control. Recently, inheritance of protective Natural Killer (NK) receptor alleles (KIR3DL1high and KIR3DS1) in conjunction with their corresponding MHC Class I HLA-Bw4 80I alleles (especially HLA-B* 57) have been found to correlate with delayed progression to AIDS. Nevertheless, characterization of the innate immune compartment (NK cells and dendritic cells) has yet to be reported in HIV-1 elite controllers. Here, we propose to measure the phenotype and function of NKs and dendritic cells (DCs) in elite controller and non-controller subjects based on our long standing work in characterizing innate immunity in HIV infected subjects and our recently described autologous HIV-1 infected CD4 primary T cell system for measuring DC-dependent NK lysis. Together, we will test the central hypothesis that increased innate effector function (DC accessory support and NK cytotoxicity) is a determinant of viral control in elite controller subjects that are KIR3DL1high or KIR3DS1 positive in conjunction with their corresponding MHC Class I HLA-Bw4 80I ligands independent of their HLA-Bw4 80I allele HLA-B*57 status. We will test this hypothesis by two aims. First, we will characterize the NK and DC subset distribution and activation potential by measuring the frequency, activation state, signaling potential and cytokine secretion capacity of plasmacytoid DCs, myeloid DCs, and NK cells. Second, we will determine constitutive and HIV-induced DC-dependent cytotoxic function of NK cells against autologous HIV-1 infected CD4 primary T cell via chromium release and CD107 degranulation assays. This proposal represents a collaboration between the University of California-San Francisco, the University of Pennsylvania and the Wistar Institute. PUBLIC HEALTH RELEVANCE: The proposed study focuses on the study of a small subset of HIV-1 infected subjects that exhibit spontaneous control of viral replication (VL<75 copies RNA/mL) in the absence of anti-retroviral therapy (elite controllers) due to the need to identify mechanism(s) of immune control over HIV-1. Our research plan will test the presence of a link between KIR/HLA genotype and NK lysis of autologous HIV-1 infected target cells to determine if genetic make-up segregates differential NK responses associated with a lack of disease progression in elite controllers. Upon completion, this proposal will provide the first evidence (or lack of thereof) for the anti-HIV function of NK cells against autologous infected targets from Elite controllers, and thus will help determine if innate immune responses are a significant anti-viral mechanism that could then be independently pursued in other patient settings of chronic HIV-1 infection.