The latency reversing agent HODHBt synergizes with IL-15 to enhance cytotoxic function of HIV-specific CD8+ T-cells
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.
Authors
- Adam R. Ward (ORCID: https://orcid.org/0000-0002-7038-5597)
- Dennis C. Copertino (ORCID: https://orcid.org/0000-0002-3217-4713)
- Alina P.S. Pang (ORCID: https://orcid.org/0000-0001-6677-7355)
- J. Natalie Howard (ORCID: https://orcid.org/0000-0002-9233-4213)
- Friederike Dündar (ORCID: https://orcid.org/0000-0002-2301-112X)
- Joseph J. Eron (ORCID: https://orcid.org/0000-0002-4938-0644)
- Deborah K. McMahon (ORCID: https://orcid.org/0000-0002-4374-3539)
- Ronald J. Bosch (ORCID: https://orcid.org/0000-0002-1774-4140)
- Paul Zumbo (ORCID: https://orcid.org/0000-0001-7234-2024)
- R. Brad Jones
- Alberto Bosque (ORCID: https://orcid.org/0000-0002-8800-2160)
- John W. Mellors (ORCID: https://orcid.org/0000-0002-3737-9742)
- Rajesh T. Gandhi (ORCID: https://orcid.org/0000-0002-9701-6062)
- Jared Weiler (ORCID: https://orcid.org/0000-0001-8347-839X)
- Callie Levinger
- Joshua C. Cyktor (ORCID: https://orcid.org/0000-0003-3601-4837)
- Bernard J. C. Macatangay (ORCID: https://orcid.org/0000-0002-0405-0991)
- Erika Benko (ORCID: https://orcid.org/0000-0002-9775-0419)
- Colin Kovacs (ORCID: https://orcid.org/0000-0003-3932-6545)
- Noemi Linden (ORCID: https://orcid.org/0000-0001-5035-6716)
- Doron Betel (ORCID: https://orcid.org/0000-0002-8006-7752)
- Carissa S. Holmberg (ORCID: https://orcid.org/0000-0001-5577-9910)
- Michael J. Corley (ORCID: https://orcid.org/0000-0001-8957-7153)
- and the SAPALDIA Team
Institutions
- University of North Carolina at Chapel Hill (US)
Publication Details
- Journal
- UNC Libraries
- Published
- 2025-09-24
- DOI
- https://doi.org/10.17615/ars3-fb87
- Citations
- 1
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Harvard University
- Harvard University Center for AIDS Research
- National Institutes of Health
- Center for AIDS Research, University of Washington
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute on Drug Abuse
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases