AZD5582 plus SIV-specific antibodies reduce lymph node viral reservoirs in antiretroviral therapy-suppressed macaques

• Type of Material: Article
• Authors: Amir Dashti, Emory University; Sophia Sukkestad, Emory University; Anna Horner, Emory University; Margaret Neja, Emory University; Zain Siddiqi, Emory University; Chevaughn Waller, Emory University; Jordan Goldy, Emory University; Dominique Monroe, Emory University; Alice Lin, Emory University; Nils Schoof, Emory University; Vidisha Singh, Emory University; Maud Mavigner, Emory University; Jeffrey D. Lifson, Frederick National Laboratory for Cancer Research; Claire Deleage, Frederick National Laboratory for Cancer Research; Marina Tuyishime, Duke University; Shane D. Falcinelli, University of North Carolina, Chapel Hill; Hannah A.D. King, National Institutes of Health; Ruian Ke, Los Alamos National Laboratory; Rosemarie Mason, National Institutes of Health; Nancie M. Archin, University of North Carolina, Chapel Hill; Richard M. Dunham, University of North Carolina, Chapel Hill; Jeffrey T. Safrit, ImmunityBio Inc.; Sherrie Jean, Emory University; Alan S. Perelson, Los Alamos National Laboratory; David M. Margolis, University of North Carolina, Chapel Hill; Guido Ferrari, Duke University; Mario Roederer, National Institutes of Health; Guido Silvestri, Emory University; Ann Chahroudi, Emory University
• Language: English
• Date: 2023-10-02
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038/s41591-023-02570-7
• Title of Journal or Parent Work: Nature Medicine
• Volume: 29
• Issue: 10
• Start Page: 2535
• End Page: 2546
• Grant/Funding Information: This research was funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health’s Office of the Director, Office of Research Infrastructure Programs, through the following grants: the Emory Consortium for Innovative AIDS Research in Nonhuman Primates (UM1 AI124436 and UM1 AI169662); CARE, a Martin Delaney Collaboratory (UM1 AI126619); the Emory CFAR (P30 AI050409); the Emory National Primate Research Center (P51 OD011132) and R37 AI157862, to A.C. Research conducted by G.F. and M.T. was partially supported by the Duke CFAR (P01 AI064518 and P01 AI162242). Portions of this work were done under the auspices of the US Department of Energy under contract 89233218CNA000001 and supported by National Institutes of Health grants R01 OD011095 and R01 AI028433 (to A.S.P.) and R01 AI152703 and U54 HL143541 (to R.K.). Research was supported, in part, by federal funds from the National Cancer Institute under contracts HHSN261200800001E and 75N91019D00024 (to J.D.L.).
• Keywords: Pharmaceutics; HIV infections
• Research Categories: Biology, Virology; Health Sciences, Immunology; Health Sciences, Pharmacology

Abstract

The main barrier to HIV cure is a persistent reservoir of latently infected CD4+ T cells harboring replication-competent provirus that fuels rebound viremia upon antiretroviral therapy (ART) interruption. A leading approach to target this reservoir involves agents that reactivate latent HIV proviruses followed by direct clearance of cells expressing induced viral antigens by immune effector cells and immunotherapeutics. We previously showed that AZD5582, an antagonist of inhibitor of apoptosis proteins and mimetic of the second mitochondrial-derived activator of caspases (IAPi/SMACm), induces systemic reversal of HIV/SIV latency but with no reduction in size of the viral reservoir. In this study, we investigated the effects of AZD5582 in combination with four SIV Env-specific Rhesus monoclonal antibodies (RhmAbs) ± N-803 (an IL-15 superagonist) in SIV-infected, ART-suppressed rhesus macaques. Here we confirm the efficacy of AZD5582 in inducing SIV reactivation, demonstrate enhancement of latency reversal when AZD5582 is used in combination with N-803 and show a reduction in total and replication-competent SIV-DNA in lymph-node-derived CD4+ T cells in macaques treated with AZD5582 + RhmAbs. Further exploration of this therapeutic approach may contribute to the goal of achieving an HIV cure.