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<sup>+</sup> T cells pose a barrier to curing HIV infection. We identify overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> T cells, facilitating CD8<sup>+</sup> T cell-mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promotes sustained skewing of CD8<sup>+</sup> 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<sup>+</sup> T cell function.
Authors
- Adam R. Ward (ORCID: https://orcid.org/0000-0002-7038-5597)
- Itzayana G. Miller (ORCID: https://orcid.org/0000-0001-9199-8985)
- Thomas R. Dilling (ORCID: https://orcid.org/0000-0001-9714-1122)
- Dennis C. Copertino (ORCID: https://orcid.org/0000-0002-3217-4713)
- Talia M. Mota (ORCID: https://orcid.org/0000-0002-8925-0158)
- Paul Zumbo (ORCID: https://orcid.org/0000-0001-7234-2024)
- Uchenna Chukwukere
- Alberto Bosque (ORCID: https://orcid.org/0000-0002-8800-2160)
- Ali Danesh
- Lynsay MacLaren Ehui
- Emma Falling Iversen (ORCID: https://orcid.org/0000-0003-2770-1942)
- Jared Weiler (ORCID: https://orcid.org/0000-0001-8347-839X)
- Nathan L. Board (ORCID: https://orcid.org/0000-0002-5208-9970)
- Khan Farzana
- Callie Levinger
- Kiera Clayton (ORCID: https://orcid.org/0009-0006-9398-0651)
- Seden Bedir (ORCID: https://orcid.org/0000-0002-8509-1268)
- R. Brad Jones
- Thaís Klevorn (ORCID: https://orcid.org/0000-0002-2765-1626)
- Mirko Paiardini (ORCID: https://orcid.org/0000-0002-7276-3600)
- Noemi Linden (ORCID: https://orcid.org/0000-0001-5035-6716)
- Louise Leyre (ORCID: https://orcid.org/0000-0002-7890-702X)
- Doron Betel (ORCID: https://orcid.org/0000-0002-8006-7752)
- Jennifer M. Johnson (ORCID: https://orcid.org/0000-0003-4548-307X)
- Sandra Terry (ORCID: https://orcid.org/0000-0003-2620-5306)
- Andrea Gramatica (ORCID: https://orcid.org/0000-0002-7131-933X)
- Andrew P. Kurland
- Yanqin Ren (ORCID: https://orcid.org/0000-0002-8054-0001)
- Colin Kovacs
- Tan Thinh Huynh
- Tyler J. Kemmer
Institutions
- University of Massachusetts Chan Medical School (US)
- George Washington University (US)
- Aarhus University (DK)
- Cornell University (US)
- Maple Leaf Medical Clinic (CA)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115652
- Citations
- 14
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 14.51
Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases