HIV reservoirs in lymphomagenesis: hidden driver in the era of viral suppression?

SUMMARY Despite advancements in antiretroviral therapy, people living with HIV (PLWH) remain at high risk of lymphoma. The persistence of HIV reservoirs and their spatial association with lymphoma highlights the need to clarify their role in lymphomagenesis. HIV reservoirs, which are established early during infection and maintained through clonal expansion, epigenetic silencing, and immune evasion, may contribute to lymphomagenesis through four interconnected mechanisms: provirus integration effects, viral protein-mediated disturbances, microenvironment dysregulation, and reservoir reactivation. Current therapeutic approaches that simultaneously target HIV reservoirs and lymphoma—including allogeneic hematopoietic stem cell transplantation, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors—show promise but face substantial challenges. There is an urgent need to develop accessible strategies that can both eradicate HIV reservoirs and mitigate lymphoma risk. Such efforts may ultimately enable a “double cure” for PLWH with lymphoma, offering new hope against this life-threatening comorbidity. This review summarizes the potential links between HIV reservoirs and HIV-associated lymphoma and outlines emerging therapeutic avenues toward achieving a double cure.