The latency-reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific T cells
Authors
Dennis C. Copertino, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Carissa S. Holmberg, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA.
Jared Weiler, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Adam R. Ward, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
J Natalie Howard, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA.
Callie Levinger, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA.
Alina Ps Pang, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Michael J. Corley, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Friederike Dündar, Applied Bioinformatics Core and.
Paul Zumbo, Applied Bioinformatics Core and.
Doron Betel, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Rajesh T. Gandhi, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
Deborah K. McMahon, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Ronald J. Bosch, Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Noemi Linden, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Bernard J. Macatangay, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Joshua C. Cyktor, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Joseph J. Eron, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
John W. Mellors, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Colin Kovacs, Maple Leaf Medical Clinic, Toronto, Ontario, Canada.
Erika Benko, Maple Leaf Medical Clinic, Toronto, Ontario, Canada.
Alberto Bosque, Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA.
R Brad Jones, Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Document Type
Journal Article
Publication Date
9-22-2023
DOI
10.1172/jci.insight.169028
Keywords
AIDS/HIV; Adaptive immunity; Cellular immune response; Immunology; Immunotherapy
Abstract
IL-15 is under clinical investigation toward the goal of curing HIV infection because of 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 cell 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 showed that ex vivo IL-15 + HODHBt treatment markedly enhanced HIV-specific granzyme B-releasing T cell responses in PBMCs from antiretroviral therapy-suppressed (ART-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 ART-suppressed donors. Our findings reveal the potential for second-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.
APA Citation
Copertino, Dennis C.; Holmberg, Carissa S.; Weiler, Jared; Ward, Adam R.; Howard, J Natalie; Levinger, Callie; Pang, Alina Ps; Corley, Michael J.; Dündar, Friederike; Zumbo, Paul; Betel, Doron; Gandhi, Rajesh T.; McMahon, Deborah K.; Bosch, Ronald J.; Linden, Noemi; Macatangay, Bernard J.; Cyktor, Joshua C.; Eron, Joseph J.; Mellors, John W.; Kovacs, Colin; Benko, Erika; Bosque, Alberto; and Jones, R Brad, "The latency-reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific T cells" (2023). GW Authored Works. Paper 3363.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/3363
Department
Microbiology, Immunology, and Tropical Medicine
