The overall goal of this proposal is to evaluate the safety and therapeutic potential of in vivo blockade of the PD-1 (Programmed death-1) co-inhibitory pathway to achieve a functional cure (long-term control in the absence of antiretroviral therapy) for HIV/AIDS using the SIV/macaque model. Dysfunctional anti-HIV immunity and persistence of viral reservoirs represent the two major issues that must be addressed by therapeutic approaches targeting functional cure. Combination antiretroviral drug therapy (ART) helps only to some extent. We believe that these two issues can be addressed effectively by targeting the PD-1 co-inhibitory pathway during ART. First, our recent studies showed that PD-1 blockade during chronic SIV infection (in the absence of ART) is safe and restores function of SIV-specific cellular and humoral immunity, improves gut permeability barrier function and prolongs survival. These results demonstrated that in vivo blockade of PD-1 represents a novel treatment strategy to restore anti-HIV immunity. Second, recent studies have demonstrated that the majority of HIV-1 latently infected cells express PD-1 and blocking PD-1 signaling on these cells reactivates the latent virus in vitro, suggesting that in vivo blockade of PD-1 may result in reactivation of the latent virus that can subsequently be cleared by the functional anti-viral immunity. Here we propose to achieve a functional cure for HIV/AIDS by combining PD-1 blockade with ART and therapeutic vaccination. This proposal has three specific aims. In aim 1, we will optimize conditions for enhancing anti-viral immunity and reducing the establishment of latently infected cells following the initiation of ART. In aim 2, we will optimize conditions to purge the viral reservoirs during ART. In aim 3, we will use the best condition from aims 1 and 2, and combine with therapeutic vaccination to achieve a functional cure. This will be a collaborative effort between Drs. Amara (Emory University), Ahmed (Emory University) and Freeman (Harvard University). If successful, our results will show a definitive path for clinical testing of PD-1 blockade combined with therapeutic vaccination to achieve a functional cure for HIV/AIDS.