This is an application for a K08 award for Dr. Devi SenGupta, an Assistant Adjunct Professor in the Division of Experimental Medicine at the University of California, San Francisco (UCSF), who is establishing herself as a young investigator studying the role of human endogenous retroviruses (HERV-K(HML-2)) in HIV infection. HERVs are remnants of ancient infections that exist as dormant elements encoded in the human genome. However, they can be reactivated in HIV infection as a result of dysregulated host defense mechanisms. The extent and consequences of HERV-K reactivation during HIV infection are incompletely understood. Dr. SenGupta has shown that HERV-specific CD8+ T cell responses are associated with control of HIV in chronic infection and has demonstrated the ability of these cells to eliminate HIV- and SIV-infected cells in vitro. These data suggest that reactivated HERVs may serve as conserved, host-encoded targets on HIV-infected cells, leading to their cytotoxic lysis, and that they can potentially be exploited in a therapeutic vaccine strategy. In addition to control of viremia, Dr. SenGupta has found that HERV-K expression is associated with decreased levels of immune activation in untreated individuals. Immune activation is a major cause of morbidity (including poor CD4+ T cell recovery on treatment) in chronic HIV. Several questions are necessary for further characterization of the complex role of HERVs in HIV infection: how does HERV-K expression in infected cells drive HERV-K-specific immunity (Aim 1)? What is the role of HERV-specific CD4+ T-helper and regulatory (Treg) cells in HIV (Aim 2)? Finally, how does HERV-K expression and the resulting adaptive immune response in early infection modulate long-term HIV disease outcome as defined by immune activation, CD4+ T cell recovery in treated subjects, and HIV viral load in untreated individuals (Aim 3)? Organized around these aims and guided by both formal coursework and mentorship, Dr. SenGupta will acquire expertise that will enable her to achieve success as an independent translational investigator. To achieve this goal, Dr. SenGupta has assembled a mentoring team comprised of a primary mentor, Dr. Douglas F. Nixon, Professor of Medicine and an expert in adaptive immune responses and HERV biology, and two co-mentors: Dr. Joseph Mike McCune, Chief of the Division of Experimental Medicine at UCSF, who conducts research in Tregs and mucosal immunity, and Dr. Steven G. Deeks, Professor of Medicine in Residence, who has specific expertise in designing and interpreting studies of well-characterized clinical cohorts of HIV-infected individuals. Dr. SenGupta's research proposal coupled with a structured training plan will allow her to develop the necessary skills and preliminary data for an R01 grant application in which she will ultimately study how HERV-K can be harnessed to create novel vaccine and eradication strategies against HIV. PROJECT NARRATIVE: HIV/AIDS remains a leading cause of morbidity and mortality in much of the world, calling for a renewed search for innovative vaccine and therapeutic strategies. A novel approach to the problem of how to empower the immune system to target the rapidly mutating human immunodeficiency virus (HIV) utilizes the HIV-driven reactivation of human endogenous retroviruses (HERVs). HERVs are fossils of ancient infections fixed in our genome, and an understanding of how HERVs might affect HIV disease and its associated over-activation of the immune system could lead to potential new therapies for millions of people around the globe.