In people living with HIV (PLWH), Hodgkin disease (HD) occurs with increased frequency compared with the general population. In the US, standardized incidence ratios for HD in PLWH vs. others is 7.6. Although HD patients with HIV (HIV-HD) respond well to standard therapies in clinical trials, in practice, HIV-HD patients demonstrate inferior outcomes in comparison to non-HIV infected patients with HD (non-HIV-HD). Non-HIV-HD is mainly confined to the lymph nodes, bone marrow (BM) involvement is much less common and BM only disease is extremely unusual. In contrast, HIV-HD displays an unusually aggressive clinical behavior with extra nodal involvement in a majority of cases. Almost half of HIV-HD patients present with BM disease at diagnosis and sometimes isolated BM involvement is the primary manifestation of the disease. The current project seeks to explore unique aspects of biology of HD in patients with HIV. To this end, HIV-HD is almost always associated with EBV infection suggesting unique mechanisms of lymphomagenesis and potentially distinct biological features of the malignant cells in these patients. In addition, the bone marrow microenvironment is profoundly remodels in PLWH and may become unusually permissive to being seeded by HD cells. Using a broad repertoire of patient derived samples and innovative in vitro and xenograft models, this group of investigators will assess the fitness of malignant cells in HIV-HD patients and how they interact with the remodeled bone marrow microenvironment from PLWH. Research proposed here will further our understanding of how the microenvironment of PLWH influences the biological and clinical behavior of HD. This group investigators have complementary expertise covering bone marrow microenvironment, biology of HIV infection, cancer stem cells of HD and the impact of EBV on viral lymphomas. They have already published together their efforts regarding the impact of HIV infection on hematopoiesis. Together with their collaborators are well situated to answer these important questions in HIV-HD.