DESCRIPTION: A major challenge in HIV research is the development of therapies to eradicate or cure established infection. Immunotherapy is one way of harnessing the immune system to target infected cells; however, this is hampered by T cell dysfunction or exhaustion. We have discovered a novel therapeutic vaccination strategy that reverses established T cell tolerance and exhaustion to self-antigen, as well as during a chronic murine viral infection resulting in the emergence of extremely large numbers of anti-viral CD8 T cells. This strategy does not rely on interfering with immune regulatory pathways and is antigen-specific, leading to expansion only of targeted T cells, while maintaining normal immune homeostasis. When SIV+ Rhesus macaques are exposed to this therapeutic vaccination platform, this results in a very large augmentation of functional SIV- specific T cells. We propose here to rigorously test the concept that antigen-specific therapeutic vaccination during established SIV infection and anti-retroviral therapy (ART) can induce large changes within the SIV+ CD8 T cell population, which can then affect and control viral recrudescence and viral reservoirs after ART removal. The underlying hypothesis is that the combination of numbers, location and function of the CTL response, along with a reduction in target cells due to ART, is the principal determinant of outcome. During the R21 phase, SIV-specific CD8 T cell numbers, phenotype and function will be evaluated during the course of vaccination. SIV viral loads will also be monitored and the effects of therapeutic vaccination on viral recrudescence will be evaluated. If outlined milestones are met, the R33 phase will expand on the positive outcome seen during the R21 phase, and also enumerate SIV-specific T cells in tissues, their relation to SIV+ cells and determine whether additional boosting events can afford greater efficacy. If our strategy is successful, we will aim to translat this type of therapeutic vaccination platform for use in HIV infected individuals.