ABSTRACT The success of antiretroviral therapy (ART) has transformed the HIV/AIDS pandemic into a life-long chronic disease, yet major challenges remain as a growing population of ~35 million patients living with HIV continues to face significant health challenges. These include side-effects and toxicity of ART, immune dysfunction and chronic inflammation that results in diseases associated with accelerated aging, and an increase in non-AIDS defining cancers. Continued infections also heighten the risk of multidrug resistance. Thus, the search for a sterilizing or functional cure that permits years of drug-free life for infected individuals has moved to center stage for HIV/AIDS research.. We now propose to contribute to the basic science that underlies these issues by: 1) Use hu-mice to determine the pathway of viral reactivation from latency at the anatomical and cellular levels, 2) Determine molecular mechanisms that are important for the establishment, maintenance, and reversal of latency, and 3) Decipher molecular mechanisms that mediate immune responses, with a focus on receptors that localize antibodies, regulate innate immunity, and localize or regulate T-cells. These studies will advance understanding of the latent reservoir, HIV gene expression, immune responses, and will inform the development of eradication strategies.