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

Authors

• Andrea Gramatica, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Itzayana G. Miller, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
• Adam R. Ward, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Farzana Khan, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Tyler J. Kemmer, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Jared Weiler, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Tan Thinh Huynh, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Paul Zumbo, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA.
• Andrew P. Kurland, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
• Louise Leyre, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
• Yanqin Ren, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Thais Klevorn, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
• Dennis C. Copertino, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Uchenna Chukwukere, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Callie Levinger, Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20052, USA.
• Thomas R. Dilling, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Noemi Linden, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
• Nathan L. Board, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Emma Falling Iversen, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
• Sandra Terry, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Talia M. Mota, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• Seden Bedir, Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
• Kiera L. Clayton, Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
• Alberto Bosque, Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20052, USA.
• Lynsay MacLaren Ehui, Whitman Walker Health, Washington, DC 20005, USA.
• Colin Kovacs, Maple Leaf Medical Clinic and Division of Infectious Diseases, Department of Medicine, University of Toronto, Toronto, ON, Canada.
• Doron Betel, Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
• Jeffry R. Johnson, Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
• Mirko Paiardini, Emory National Primate Research Center, Emory University, Atlanta, GA 30322 USA; Department of Pathology & Laboratory Medicine, Emory School of Medicine, Emory University, Atlanta, GA 30322, USA.
• Ali Danesh, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
• R Brad Jones, Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA; Department of Microbiology and Immunology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: rbjones@med.cornell.edu.

Document Type

Journal Article

Publication Date

5-5-2025

Journal

Cell reports

Volume

44

Issue

5

DOI

10.1016/j.celrep.2025.115652

Keywords

CP: Immunology; CP: Microbiology; EZH2; HIV; HIV cure research; HIV reservoir; T cell exhaustion; T cell immunity; epigenetic regulation; tazemetostat

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.

APA Citation

Gramatica, Andrea; Miller, Itzayana G.; Ward, Adam R.; Khan, Farzana; Kemmer, Tyler J.; Weiler, Jared; Huynh, Tan Thinh; Zumbo, Paul; Kurland, Andrew P.; Leyre, Louise; Ren, Yanqin; Klevorn, Thais; Copertino, Dennis C.; Chukwukere, Uchenna; Levinger, Callie; Dilling, Thomas R.; Linden, Noemi; Board, Nathan L.; Falling Iversen, Emma; Terry, Sandra; Mota, Talia M.; Bedir, Seden; Clayton, Kiera L.; Bosque, Alberto; MacLaren Ehui, Lynsay; Kovacs, Colin; Betel, Doron; Johnson, Jeffry R.; Paiardini, Mirko; Danesh, Ali; and Jones, R Brad, "EZH2 inhibition mitigates HIV immune evasion, reduces reservoir formation, and promotes skewing of CD8 T cells toward less-exhausted phenotypes" (2025). GW Authored Works. Paper 7300.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/7300

Department

Microbiology, Immunology, and Tropical Medicine