The EZH2 inhibitor tazemetostat mitigates HIV immune evasion, reduces reservoir formation, and promotes durable CD8+ T-cell revitalization
Gramatica, A.; Miller, I. G.; Ward, A. R.; Khan, F.; Kemmer, T. J.; Weiler, J.; Huynh, T. T.; Zumbo, P.; Kurland, A. P.; Leyre, L.; Ren, Y.; Klevorn, T.; Copertino, D. C.; Chukwukere, U.; Levinger, C.; Dilling, T. R.; Linden, N. L.; Board, N. L.; Falling Iversen, E.; Terry, S.; Mota, T. M.; Bedir, S.; Clayton, K. L.; Bosque, A.; MacLaren Ehui, L.; Kovacs, C. M.; Betel, D.; Johnson, J. R.; Paiardini, M.; Danesh, A.; Jones, R. B.
Show abstract
Persistent HIV reservoirs in CD4 T-cells pose a barrier to curing HIV infection. We identified 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 FDA-approved drug tazemetostat increased surface expression of major histocompatibility complex class I (MHC-I) on CD4 T-cells, counterbalancing HIV Nef-mediated MHC-I downregulation. This improved CTL-mediated elimination of HIV-infected cells and suppressed viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevated MHC-I and the pro-apoptotic protein BIM in CD4 T-cells, facilitating CD8 T-cell-mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promoted sustained skewing of CD8 T-cells toward less differentiated and exhausted phenotypes. Our findings reveal EZH2 overexpression as a novel mechanism of CTL resistance and support the clinical evaluation of tazemetostat to enhance clearance of HIV reservoirs and improve CD8+ T-cell function.
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