Cancer is the leading cause of death in people living with HIV (PLWH) in the United States and worldwide despite combination antiretroviral therapy (cART). Although the incidences of AIDS-defining malignancies have declined since the advent of cART, a number of non-AIDS–defining cancers (NADCs) appear more common in HIV-1–infected individuals relative to the general population. Hodgkin’s lymphoma (HL) represents one of the most common types of NADCs that occurs in HIV-infected individuals. The incidence of HL is 10-fold higher in PLWH relative to the general population, and the frequency of this malignancy is actually increasing in the postcART era. Several factors are associated with the rising rate in HL, but two key features are accelerated immunological aging and HIV infection, suggesting that there is interplay between HIV and immune senescence that results in an escalating occurrence of cancer development and progression. We and others have identified specific epigenetic changes associated with aberrant T cell replicative capacity that are also altered in cancer, chronic viral infection, inflammatory diseases and aging. Published work, together with our preliminary singlecell RNA sequencing studies suggest that CD8+ T cells responsible for tumor control in HL exhibit several abnormalities, including a more advanced differentiation state, poor proliferative capacity and downregulation of several genes that negatively regulate cellular senescence. The presence of a characteristic inflammatory microenvironment is a fundamental component of the tumor mass and an essential pathogenic factor in HL. In chronic HIV infection, a similar accumulation of senescent and activated CD8+ T cells and increasing levels of inflammatory factors are linked to higher risks of morbidity and mortality, indicating that specific disease processes (e.g., inflammation) likely underlie HIV-associated epigenetic changes and concomitant immunosenescence. Thus, HIV and lymphoma may have an additive influence on overlapping epigenetic pathways to accelerate aging-induced immune deterioration, resulting in loss of tumor control. However, important gaps exist in our understanding of the fundamental nature and underlying mechanisms of T cell senescence in HIV and cancer, and how those in turn, influence anti-tumor immunity; this hampers our practical ability to clinically manage these diseases and develop new effective therapies. This pilot proposal is responsive to the NIH HIV/AIDS Research High Priorities (as listed in NOT-OD15-137) through expansion of knowledge regarding the impact of pre-mature immunological aging in long-term HIV disease and the pathogenesis of NADCs. Our approach benefits from a longstanding interest in cellular immunology and determining the molecular underpinnings of age-induced immune decline in the setting of oncogenesis, tumor progression and therapeutic responses. In this vein, we recently established and operationalized a pipeline that incorpora...