PROJECT SUMMARY: Approximately 1.2 million people are currently living with HIV (PLWH) in the United States. These individuals are at an elevated risk for various cancers, particularly B-cell non-Hodgkin lymphomas (BCLs), such as diffuse large B-cell lymphoma and Burkitt lymphoma. These lymphomas often display comorbidity with Epstein-Barr virus infection (EBV). The use of combinatorial antiretroviral therapy (cART) has been shown to effectively control HIV replication, leading to restored immune function and decreased cancer rates in PLWH. Moreover, the latest developments in cancer treatment, along with cART, have significantly increased the success rates for PLWH battling cancer. Despite such advancements in treatment and improved survival rates, effectively managing cancers in PLWH demands a comprehensive approach – one that takes into consideration the specific traits of these malignancies when in the presence of HIV. HIV and EBV, which solely infect human hosts, create a unique obstacle in the development of in vivo models for assessing potential cancer therapies. Humanized mice with a functional human blood system offer a valuable model for studying immunotherapeutic approaches for BCLs under HIV and EBV co-infection. Through our recent single-cell transcriptomics analysis of humanized mice, we have discovered that the NSG-SGM3 mouse outperforms the standard NSG mouse in its ability to mimic various types of human blood cells found in human peripheral blood. Developing a murine model with a realistic human tumor microenvironment largely relies on this critical factor. This model is integral in evaluating the effectiveness of immune-based cancer therapies and monitoring immunological changes throughout treatment. The proposed study aims to confirm the effectiveness of new CAR-T cell approaches for treating BCLs in the presence of HIV while examining its immunological impact using a humanized NSG-SGM3 mouse model.