PROJECT SUMMARY/ABSTRACT Although an effective vaccine remains the best long-term solution to halt the spread of HIV, we still do not know how to elicit protective immune responses against this virus. Encouragingly, recent breakthroughs in the field of immuno-oncology have uncovered opportunities to enhance vaccine immunity by directly targeting immuno- modulatory pathways (termed ?immune checkpoints?). For example, while the co-inhibitory receptor cytotoxic T- lymphocyte antigen-4 (CTLA-4) aids in the prevention of excessive immune activation, it can also dampen desirable immune responses, such as those engendered by vaccination. Consequently, blocking CTLA-4 during vaccination has been shown to augment both cellular and humoral responses in animal models. In cancer patients, treatment with the FDA-approved, CTLA-4-specific antibody Ipilimumab can unleash the effector functions of T-cells against tumors, leading to tumor regression and longer patient survival. Based on these potent immune stimulatory effects, the goal of this project is to test the efficacy of a prophylactic, Ipilimumab- adjuvanted HIV vaccine using the simian immunodeficiency virus (SIV)/rhesus macaque model. In addition to clarifying how CTLA-4 blockade impacts the induction of antiviral immunity, this K01 career development award will bring me closer to my long-term goal of leading a productive research program on HIV immunology. Importantly, this project will benefit from the mentorship of Dr. David Watkins, Dr. Ron Desrosiers, and Dr. Julie McElrath?three outstanding investigators in the field of HIV/AIDS vaccine development. The collaborative environment in place for the Watkins and Desrosiers labs at the University of Miami, and the state of the art animal facilities at the Wisconsin National Primate Research Center, will greatly facilitate the execution of the proposed research. To address the hypothesis that priming immune responses during CTLA-4 blockade can improve vaccine efficacy against SIV, two groups of rhesus macaques will be vaccinated with a novel heterologous prime-boost regimen. While the Group 1 vaccinees will be treated with Ipilimumab during the priming phase, the Group 2 macaques will be vaccinated in the absence of anti-CTLA-4 therapy. Ultimately, vaccinees in Groups 1 and 2, as well as a group of control monkeys (Group 3), will be challenged intra-rectally with a pathogenic molecular clone of SIV. This project has three specific aims: 1) Determine if CTLA-4 blockade can broaden vaccine-induced, SIV-specific T-cell responses; 2) Examine if CTLA-4 blockade can enhance the generation of Env-specific antibodies by vaccination; and 3) Assess if priming antiviral immunity during CTLA-4 blockade can improve vaccine efficacy against SIV challenge. If inhibiting CTLA-4 during vaccination enhances protection against SIV, the implications of this finding will be far reaching. Not only would this discovery guide the design of future vaccine strategies against HIV, but it would also prompt the evaluation of additional immune checkpoint inhibitors as prophylactic vaccine adjuvants.