Abstract Candidate: The objective of this K01 SERCA application is to provide the mentorship, support, and protected time necessary for Dr. Sarah Beck, DVM, PhD, DACVP to progress into a successful and productive career in independent translational research in the field of vaccine immunology. Dr. Beck is a veterinarian with extensive experience in viral immunology and nonhuman primate models of simian immunodeficiency virus (SIV). Her training at Johns Hopkins has provided her with expertise in a wide variety of animal models and comparative pathology, and she also is a Diplomate in the American College of Veterinary Pathologists (ACVP), making her a uniquely qualified candidate for translational research. Under the mentorship of a well-rounded and experienced scientific advisory committee and her co-mentors, Dr. Joel Blankson and Dr. Joseph Mankowski, the proposed training will allow her to expand her expertise into the field of vaccine immunology and the use of humanized mouse models of viral immunopathogenesis. Research Plan: Despite the fact that combined antiretroviral therapy is able to control viral replication and prolong the life of HIV infected individuals, HIV remains a pandemic without a cure. One of the largest blockades to achieving HIV cure is proving to be the presence of virus in resting CD4+ T cell reservoirs. Myriad studies have identified cell-mediated immunity (CMI) as an important mechanism for controlling viral replication. Although effective combined antiretroviral therapy (cART) prevents new rounds of HIV infection, it is incapable of eliminating pre-existing infected CD4+ cells, which are the most likely precursors to the majority of latently infected cells. In contrast, CD8+ T cells are capable of eliminating either productively infected or non-productively infected cells. This approach is supported by recent data using a CMV-based HIV vaccine, which showed that the presence of vaccine-induced CD8+ T cells in primary infection in SIV-infected rhesus were able to eliminate the viral reservoir entirely. The development of broad, persistent HIV Gag-specific CTL responses is believed to play a major role in control of viral replication and determination of clinical outcome. With this in mind, Dr. Beck plans to induce a robust, broad, HIV Gag-specific CD8+ T cell response using a novel virus like protein (VLP) platform with the goal of reducing or eliminating the viral reservoir by inducing effective CTL-mediated control of viral replication in primary HIV infection. This VLP vaccination strategy has several advantages over other vaccine strategies: 1) this VLP is a subunit type vaccine constructed on a bovine papillomavirus capsid, which is a foreign antigen to mice, monkeys, or humans, and therefore can be used across species easily, 2) it preferentially stimulates CTL response over humoral responses, and 3) it is able to induce a strong effector memory response. The overarching hypothesis of the proposed studies is that v...