Project Summary Effective antiretroviral therapy (ART) for people with HIV (PWH) has increased in the last 20 years, resulting in increased life expectancy and reduced mortality by 61% since its peak in 2004. As of 2016, nearly 50% of PWH in the United States were older than 50 years of age. Within this older population of PWH, age-associated comorbidities, including non-AIDS-defining cancers, are disproportionately higher than otherwise predicted. Even in the ART era, PWH are at increased risk for Hodgkin and non-Hodgkin lymphoma and endure substantially higher mortality from lymphoma than HIV-negative individuals. CD38 is a T cell marker that increases with HIV infection, cancer, and age, and is not normalized with use of ART and viral suppression. CD38 is overexpressed in lymphoma and persists due to chronic antigen stimulation and promotes tumor growth via dysregulated production of tumor-promoting cytokines, making it a proposed target for lymphoma treatment. In addition to being a lymphocyte marker, CD38 is also an ectoenzyme that is mainly responsible for catalyzing intracellular nicotinamide adenine dinucleotide (NAD+). NAD+, like CD38, has been linked to multiple pathways underlying tumor growth, and studies of animal models have suggested that increasing intracellular NAD+ levels may prevent cancer. Currently, there are no data on how CD38 influences tumor growth in PWH or how targeting CD38 can reverse its effect. We hypothesize that exacerbated CD38 expression in PWH is a crucial factor for promoting tumor growth and is associated with effector T cell dysfunction. We plan to test our hypothesis using two experimental models. First, we will determine if CD38 is associated with effector T cell dysfunction (by measuring checkpoint proteins) and production of tumor-promoting cytokines using blood and lymphoma tissue samples from PWH and HIV-negative controls at least 50 years of age. Next, using an HIV-infected humanized mouse model with lymphoma, we will target CD38 directly and indirectly by using a monoclonal antibody against CD38 and NAD+ precursor. We will determine which strategy results in maximal tumor growth inhibition with minimal toxicity. We expect to demonstrate that PWH have exacerbated CD38 expression in lymphoma. Second, we expect to demonstrate that in PWH and lymphoma, increased CD38 expression on effector T cells are associated with increased checkpoint proteins and increased production of tumor-promoting cytokines. Last, we expect to demonstrate that targeting CD38 may be a potential therapeutic adjunct to chemotherapy and ART for PWH with lymphoma. The goals of this proposal directly align with the NIH HIV/AIDS Research Priority as described in NOT-OD-20-018, as it investigates virus/host cell interactions and pathogenesis (the interplay between HIV and host CD38), immune dysfunction and persistent inflammation, and long-term treatment or prevention strategies for HIV-relevant comorbid condit...