{"doi":"10.1016/j.celrep.2025.115652","title":"EZH2 inhibition mitigates HIV immune evasion, reduces reservoir formation, and promotes skewing of CD8+ T cells toward less-exhausted phenotypes","abstract":"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.","journal":"Cell Reports","year":2025,"id":510811,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9553,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":809974,"name":"Itzayana G. 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