Immune activation and HIV disease progression are tightly linked, suggesting that interfering with the factors that continually stimulate the immune response could have tremendous therapeutic benefit. Yet, the precise mechanisms underlying immune activation, how it contributes to immune deterioration, the ability to therapeutically interfere with this process, and whether blocking immune activation could restore immune competence are all unclear. Thus, there are many critical questions that must be addressed before this potentially important therapeutic strategy can be effectively implemented. Across multiple species, including mouse models of chronic virus infection, SIV infection in primates, and HIV infection in humans, mounting evidence implicates chronic type I interferon (IFN-I) signaling as a central mechanism driving immune activation, dysfunction, and ultimately viral persistence and disease progression. The goal of this proposal is to understand the relationship between chronic IFN-I signaling, immune activation, and immune dysfunction during HIV infection and implement a therapeutic strategy to inhibit IFN-I signaling to restore immune function and control HIV infection. To achieve this goal, we will utilize humanized mice that recapitulate IFN-I induced immune activation in vivo and an innovative approach to specifically generate HIV-specific T cells to: (1) define the precise IFN-I mediated targets of immune activation and dysfunction during HIV infection;(2) inhibit IFN-I in vivo to reverse chronic immune activation and enhance HIV-specific T cell immunity;and (3) determine the virologic impact of blocking IFN-I. Once completed, our studies will significantly advance our understanding of HIV:immune interactions that potentiate viral persistence and provide the foundation, rationale, and system for future studies to define and target immune activation during HIV infection.

Public Health Relevance

Understanding the immunologic and virologic mechanisms of HIV disease is critical to identify novel targets for therapeutic intervention. Chronic immune activation during HIV infection is highly associated with multiple immunologic dysfunctions and is a strong correlate of disease progression. We will investigate the critical role of prolonged type I interferon signaling in driving disease progression during HIV infection in vivo and develop a novel system to therapeutically abolish chronic immune activation to restore immune competence to fight HIV infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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AIDS Immunology and Pathogenesis Study Section (AIP)
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Conley, Tony J
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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