Immune dysfunction experienced by people living with HIV (PLWH) results in accelerated aging that may negatively impact clinical outcomes. Preliminary data from studies of PLWH provide evidence of accelerated epigenetic aging in the setting of HIV, and this accelerated aging has been linked to a 19% increased mortality risk. We will compare age-related clonal hematopoiesis (ARCH) between 75 PLWH and cancer and 75 HIV-uninfected cancer patients who were treated at Moffitt for a non-AIDS-defining cancer (NADC). ARCH is a somatic mutation rate that is strongly correlated with chronological age in the general population and has been linked to inflammation, mortality, and development of refractory complications following cancer therapy. We hypothesize that ARCH will be uniquely elevated in PLWH and that this agerelated mutation rate will be associated with poor clinical outcome in PLWH and cancer. In Aim 1, we will compare ARCH mutations present in peripheral blood at NADC diagnosis between patients with versus without HIV, with HIV-uninfected patients matched to PLWH on disease site and stage, chronological age, and reported smoking status. In Aim 2, we will examine the association between ARCH at cancer diagnosis and clinical outcomes (mortality, locoregional recurrence/metastasis, subsequent cancer), including outcomes specific to PLWH and cancer. In Aim 3, we will assess whether ARCH mutations present at NADC diagnosis evolve at different rates during cancer therapy by HIV status through comparison of mutation frequency in peripheral blood at cancer diagnosis and then again post-therapy. Our research team is uniquely positioned to undertake this research, combining expertise in HIV and malignancy (Dr. Coghill) and clonal hematopoiesis (Dr. Gillis) research, with the support of Center Director Dr. John Cleveland. The infrastructure to obtain samples, perform sequencing and analysis, and assess clinical outcomes is supported by shared Core facilities funded by Moffitt, including the Molecular Genomics Core, Tissue Core, Biostatistics/Bioinformatics Core, and Collaborative Data Services. This project addresses the following high-priority area listed in NOT-OD-15-137: HIV-associated comorbidities and complications, including accelerated aging and malignancy in PLWH. Successful conduct of this study will serve as the foundation for larger, more definitive evaluations of aging in the context of HIV and cancer.