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

Dashti, Amir; Sukkestad, Sophia; Horner, Anna M.; Neja, Margaret; Siddiqi, Zain; Waller, Chevaughn; Goldy, Jordan; Monroe, Dominique; Lin, Alice; Schoof, Nils; Singh, Vidisha; Mavigner, Maud; Lifson, Jeffrey D.; Deleage, Claire; Tuyishime, Marina; Falcinelli, Shane D.; King, Hannah A. D.; Ke, Ruian; Mason, Rosemarie D.; Archin, Nancie M.; Dunham, Richard M.; Safrit, Jeffrey T.; Jean, Sherrie; Perelson, Alan S.; Margolis, David M.; Ferrari, Guido; Roederer, Mario; Silvestri, Guido; Chahroudi, Ann

doi:10.1038/s41591-023-02570-7

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

Journal Article · Mon Oct 02 00:00:00 EDT 2023 · Nature Medicine

DOI:https://doi.org/10.1038/s41591-023-02570-7· OSTI ID:2469618

^[1]; ^[1]; Horner, Anna M. ^[1]; Neja, Margaret ^[1]; Siddiqi, Zain ^[1]; Waller, Chevaughn ^[1]; Goldy, Jordan ^[1]; ^[1]; Lin, Alice ^[1]; Schoof, Nils ^[1]; Singh, Vidisha ^[1]; Mavigner, Maud ^[1]; Lifson, Jeffrey D. ^[2]; ^[2]; Tuyishime, Marina ^[3]; ^[4]; King, Hannah A. D. ^[5]; ^[6]; Mason, Rosemarie D. ^[7]; Archin, Nancie M. ^[4] more »

Emory Univ., Atlanta, GA (United States)
Frederick National Lab. for Cancer Research, Frederick, MD (United States)
Duke Univ., Durham, NC (United States)
University of North Carolina, Chapel Hill, NC (United States)
National Institutes of Health (NIH), Bethesda, MD (United States); Walter Reed Army Institute of Research, Silver Spring, MD (United States); Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD (United States)
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
National Institutes of Health (NIH), Bethesda, MD (United States)
University of North Carolina, Chapel Hill, NC (United States); ViiV Healthcare, Research Triangle Park, NC (United States)
ImmunityBio, Inc., Culver City, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: 89233218CNA000001

OSTI ID:: 2469618

Journal Information:: Nature Medicine, Journal Name: Nature Medicine Journal Issue: 10 Vol. 29; ISSN 1078-8956

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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