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

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

doi:10.1038/s41591-023-02570-7

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

Nat Med. 2023 Oct;29(10):2535-2546. doi: 10.1038/s41591-023-02570-7. Epub 2023 Oct 2.

Authors

Amir Dashti¹, Sophia Sukkestad¹, Anna M Horner¹, Margaret Neja¹, Zain Siddiqi¹, Chevaughn Waller¹, Jordan Goldy¹, Dominique Monroe¹, Alice Lin¹, Nils Schoof¹, Vidisha Singh¹, Maud Mavigner^{1

2

3}, Jeffrey D Lifson⁴, Claire Deleage⁴, Marina Tuyishime⁵, Shane D Falcinelli⁶, Hannah A D King^{7

8

9}, Ruian Ke¹⁰, Rosemarie D Mason⁷, Nancie M Archin⁶, Richard M Dunham^{6

11}, Jeffrey T Safrit¹², Sherrie Jean², Alan S Perelson¹⁰, David M Margolis⁶, Guido Ferrari^{5

13}, Mario Roederer⁷, Guido Silvestri², Ann Chahroudi^{14

15

16}

Affiliations

¹ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
² Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
³ Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta and Emory University, Atlanta, GA, USA.
⁴ AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁵ Department of Surgery, Duke University Medical Center, Durham, NC, USA.
⁶ UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
⁸ US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁹ Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
¹⁰ Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
¹¹ HIV Drug Discovery, ViiV Healthcare, Research Traingle Park, NC, USA.
¹² ImmunityBio, Inc., Culver City, CA, USA.
¹³ Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA.
¹⁴ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. ann.m.chahroudi@emory.edu.
¹⁵ Emory National Primate Research Center, Emory University, Atlanta, GA, USA. ann.m.chahroudi@emory.edu.
¹⁶ Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta and Emory University, Atlanta, GA, USA. ann.m.chahroudi@emory.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anti-Retroviral Agents / pharmacology
Anti-Retroviral Agents / therapeutic use
Antibodies / therapeutic use
CD4-Positive T-Lymphocytes
HIV Infections*
HIV-1*
Lymph Nodes
Macaca mulatta
Simian Acquired Immunodeficiency Syndrome*
Simian Immunodeficiency Virus* / physiology
Viral Load
Virus Latency
Virus Replication

Substances

N,N'-(2,2'-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(1-(2-cyclohexyl-2-(2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide)
Anti-Retroviral Agents
Antibodies

Abstract

Publication types

MeSH terms

Substances

Grants and funding