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

Autor: Copertino DC Jr; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA., Holmberg CS; Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA., Weiler J; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA., Ward AR; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.; Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA., Howard JN; Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA., Levinger C; Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA., Pang AP; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA., Corley MJ; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA., Dündar F; Applied Bioinformatics Core and.; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York, USA.; Catenion GmbH, Berlin, Germany., Zumbo P; Applied Bioinformatics Core and., Betel D; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.; Applied Bioinformatics Core and.; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA., Gandhi RT; Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA., McMahon DK; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Bosch RJ; Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA., Linden N; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA., Macatangay BJ; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Cyktor JC; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Eron JJ; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Mellors JW; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Kovacs C; Maple Leaf Medical Clinic, Toronto, Ontario, Canada., Benko E; Maple Leaf Medical Clinic, Toronto, Ontario, Canada., Bosque A; Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC, USA., Jones RB; Infectious Diseases Division, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2023 Sep 22; Vol. 8 (18). Date of Electronic Publication: 2023 Sep 22.
DOI: 10.1172/jci.insight.169028
Abstrakt: 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.
Databáze: MEDLINE