Project Summary HIV is a disease of inflammation and chronic immune activation. Ultimately, this results in severe immune dysfunctions and occurrence of other comorbidities, including cancer. In HIV disease, the mechanisms underlying chronic inflammation and how they contribute to immune deterioration and increased risk in cancer diseases as well as whether the ability to therapeutically interfere with this process could restore immune competence remain unclear. Across multiple species, including mouse models of chronic virus infection, SIV infection in primates, and HIV infection in humans, mounting evidence implicates type I interferon (IFN-I) signaling as a central mechanism underlying the chronic inflammation that drives the development of suppressive immune environment that promote cancer growth. The goal of this proposal is to elucidate the relationship between chronic IFN-I signaling, inflammation, immune exhaustion, and the development of an immuno-suppressive tumor niche that favors tumor growth. To achieve this goal, we will utilize a humanized mouse model that 1) allows engraftment and growth of multiple tumor cell lines and 2) recapitulates IFN-I induced immune activation and exhaustion during chronic HIV infection in vivo. We will utilize novel strategies to promote or block IFN-I signaling in vivo and an innovative approach to specifically generate tumor specific T cells to: (1) define the precise contribution of IFN-I signaling during HIV infection to the development of immuno-suppressive tumor enviroment and exhaustion of anti-tumor T cell that favor cancer growth; and (2) investigate if blocking chronic IFN-I signaling during chronic HIV infection can improve anti-tumor immunity and efficacy of immune checkpoint inhibitor blockade. Once completed, we strongly feel that our studies will significantly advance the understanding of the fundamental mechanisms that result in immune dysfunction and increased risk of AIDS and non-AIDS-related cancer. This will also provide the foundation, rationale, and system for future studies to define and therapeutically target inflammation and immune activation for cancer treatment with HIV infection.