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

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.

Department

Microbiology, Immunology, and Tropical Medicine

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