Project Summary/Abstract Kidney transplantation (KT) is a lifesaving intervention for the 10,000 people living with HIV (PLWH) and end- stage renal disease in the United States. Confirmed as safe and effective in the early 2000s, this practice has rapidly expanded in the past decade amid transformative antiviral advances for HIV and hepatitis C (HCV) as well as passage of the HIV Organ Policy Equity (HOPE) Act permitting HIV-to-HIV transplantation. Despite the complex nature of this vulnerable population, neither the landscape of serious infections nor an understanding of optimal immunosuppression to balance infection and kidney rejection risk has been defined. It is critical to understand this paradigm as infection causes >20% of early deaths following KT and rejection, which results in immunosuppressive intensification and a more susceptible host, is 2-4-fold more common in HIV+ KT recipients. The goals of this proposal include characterizing the burden, timing, and spectrum of serious infections after HIV+ KT with comparison to matched HIV- KT recipients to understand differential risks associated with recipient HIV status (Aim 1). This will be accomplished through development of the largest cohort of HIV+ KT recipients to date by linking the Scientific Registry of Transplant Recipients and the US Renal Data System, which also incorporates Centers for Medicare and Medicaid claims data to ascertain serious infection events. Pharmacy clearinghouse data will augment infection, rejection, and antimicrobial prophylaxis ascertainment. Next, among the population of HIV+ KT recipients, a risk factor analysis will be performed with focus on biological variables and immunosuppressive regimens associated with developing serious post-transplant infections (Aim 2). The goal of this analysis is to inform targeted monitoring and prophylaxis to prevent infectious complications in HIV+ KT recipients. Finally, the association of donor HIV status with serious infection risk will be explored through the robust infrastructure of the ongoing HOPE in Action multicenter clinical trials of HIV-to-HIV KT (NCT03500315, Aim 3). This analysis will incorporate rich data on HIV+ organ donors and recipients including hitherto unexplored HIV biology and laboratory markers, in the context of robust infection and rejection reporting. Taken together, this proposal seeks to delineate the landscape of serious infection among PLWH undergoing KT in the modern era using a comprehensive infection ascertainment schema and rigorous epidemiologic methods. Ultimately, the goal is to advance understanding of infectious complications in this unique and emerging group and drive evidence-based practices that improve long-term post-KT outcomes.