This proposal aims to develop an effective therapy to achieve HIV remission by improving the magnitude, breadth, and function of anti-viral CD8 T cells and reducing viral reservoirs using the SIV/macaque model. Dysfunctional anti-HIV immunity and the persistence of viral reservoirs represent two major issues that must be addressed by therapeutic approaches targeting functional cure for HIV. We believe that these two issues can be addressed effectively using a combination of vaccination and inhibiting the programmed death-1 co-inhibitory pathway (PD-1 blockade). Accordingly, during the past 9 years of this R37, we invested major efforts to comprehensively define the influence of the timing of PD-1 blockade at different stages of chronic SIV infection and during anti-retroviral therapy (ART) on restoring CD8 T cell function and diminishing viral reservoirs. We also tested the influence of combining PD-1 blockade with vaccination. These results showed that a combination of therapeutic vaccination under ART and PD-1 blockade post analytical treatment interruption (ATI) leads to a profound control of reemerging viremia with some animals suppressing viremia to below the level of detection for up to 24 weeks. These results demonstrated the utility of this combination approach towards achieving HIV remission. Our recent data in mice showed that the addition of IL-2 cytokine therapy to PD-1 blockade markedly enhances the induction of highly functional effector cells and modulates their differentiation program leading to better control of LCMV infection. Based on these exciting results, we propose to improve the therapeutic potential of PD-1 blockade by combining it with IL-2 cytokine therapy. We propose 3 specific aims. In Aim 1, we will determine the safety and therapeutic efficacy of a combination of PD-1 blockade and IL-2 cytokine therapy post ATI in SIV infected and vaccinated macaques. In Aim 2, we will define the heterogeneity of exhausted CD8 T cells during chronic SIV infection and define how PD-1 blockade with and without IL-2 will modify the T cell exhaustion program. In Aim 3, we will test if an improved therapeutic vaccine combined with PD-1 blockade plus IL-2 therapy can enhance control of reemerging SIV viremia. This will be a collaborative effort between Amara (Emory), Ahmed (Emory), and Freeman (Harvard) laboratories. All three labs have worked together for over 15 years to optimize the PD-1 blockade to treat chronic SIV infection. By the completion of these aims, we hope to develop potent immunotherapy to achieve profound and sustained control of SIV infection in the absence of ART therapy.