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

作者：Dennis C. Copertino, Colin Kovacs, John W. Mellors, Alina P.S. Pang, and the SAPALDIA Team, Michael J. Corley, J. Natalie Howard, Carissa S. Holmberg, Paul Zumbo, Joseph J. Eron, Rajesh T. Gandhi, Alberto Bosque, Erika Benko, R. Brad Jones, Callie Levinger, Adam R. Ward, Bernard Macatangay, Ronald J. Bosch, Deborah K. McMahon, Jared Weiler, Joshua C. Cyktor, Noemi Linden, Doron Betel, Friederike Dündar · 发表于：UNC Libraries · 年份：2025 · DOI：10.17615/ars3-fb87 · 被引用次数：1 · 研究领域：Immune Cell Function and Interaction、Tryptophan and brain disorders、HIV Research and Treatment

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.