EZH2 inhibition mitigates HIV immune evasion, reduces reservoir formation, and promotes skewing of CD8+ T cells toward less-exhausted phenotypes.

Persistent HIV reservoirs in CD4⁺ T cells pose a barrier to curing HIV infection. We identify overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4⁺ T cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the US Food and Drug Administration-approved drug tazemetostat increases surface expression of major histocompatibility complex (MHC) class I on CD4⁺ T cells, counterbalancing HIV Nef-mediated MHC class I downregulation. This improves CTL-mediated elimination of HIV-infected cells and suppresses viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevates MHC class I and the pro-apoptotic protein BIM in CD4⁺ T cells, facilitating CD8⁺ T cell-mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promotes sustained skewing of CD8⁺ T cells toward less-differentiated and exhausted phenotypes. Our findings reveal EZH2 overexpression as a mechanism of CTL resistance and support the clinical evaluation of tazemetostat as a method of enhancing clearance of HIV reservoirs and improving CD8⁺ T cell function.