The latency reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific CD8+ T-cells

Dennis C. Copertino, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
Carissa S. Holmberg, Department of Microbiology and Immunology, The George Washington University, Washington, United States of America.
Jared Weiler, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
Adam R. Ward, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
J Natalie Howard, Department of Microbiology and Immunology, The George Washington University, Washington, United States of America.
Callie Levinger, Department of Microbiology and Immunology, The George Washington University, Washington, United States of America.
Alina Ps Pang, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
Michael J. Corley, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
Friederike Dündar, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
Paul Zumbo, Department of Physiology and Biophysics, Weill Cornell College of Medicine, New York, United States of America.
Doron Betel, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
Rajesh T. Gandhi, Infectious Disease, Massachusetts General Hospital, Boston, United States of America.
Deborah K. McMahon, Infectious Diseases, University of Pittsburgh, Pittsburgh, United States of America.
Ronald J. Bosch, Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, United States of America.
Noemi Linden, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.
Bernard J. Macatangay, Infectious Diseases, University of Pittsburgh, Pittsburgh, United States of America.
Joshua C. Cyktor, Infectious Diseases, University of Pittsburgh, Pittsburgh, United States of America.
Joseph J. Eron, UNC Chapel Hill, Chapel Hill, United States of America.
John W. Mellors, Infectious Diseases, University of Pittsburgh, Pittsburgh, United States of America.
Colin Kovacs, Maple Leaf Medical Clinic, Toronto, Canada.
Erica Benko, Maple Leaf Medical Clinic, Toronto, Canada.
Alberto Bosque, Department of Microbiology and Immunology, The George Washington University, Washington, United States of America.
R Brad Jones, Infectious Diseases Division, Department of Medicine, Weill Cornell College of Medicine, New York, United States of America.

Document Type

Journal Article

Publication Date

8-15-2023

Journal

JCI insight

DOI

10.1172/jci.insight.169028

Keywords

AIDS/HIV; Adaptive immunity; Cellular immune response; Immunology; Immunotherapy

Abstract

IL-15 is under clinical investigation towards the goal of curing HIV infection, due to its abilities to reverse HIV latency and enhance immune effector function. However, increased potency through combination with other agents may be needed. 3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HODHBt) enhances IL-15-mediated latency reversal and NK function, by increasing STAT5 activation. We hypothesized that HODHBt would also synergize with IL-15, via STAT5, to directly enhance HIV-specific cytotoxic T-cell responses. We show that ex vivo IL-15+HODHBt treatment markedly enhances HIV-specific granzyme B-releasing T-cell responses in PBMCs from ARV-suppressed donors. We also observed upregulation of antigen processing and presentation in CD4+ T-cells, and increased surface MHC-I. In ex vivo PBMCs, IL-15+HODHBt was sufficient to reduce intact proviruses in 1 of 3 ARV-suppressed donors. Our findings reveal the potential for 2nd-generation IL-15 studies incorporating HODHBt-like therapeutics. Iterative studies layering on additional latency reversal or other agents are needed to achieve consistent ex vivo reservoir reductions.

Department

Microbiology, Immunology, and Tropical Medicine

Link to Full Text

Share

COinS