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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.
Afiliação
  • Dashti A; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Sukkestad S; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Horner AM; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Neja M; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Siddiqi Z; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Waller C; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Goldy J; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Monroe D; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Lin A; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Schoof N; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Singh V; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Mavigner M; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
  • Lifson JD; Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
  • Deleage C; Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta and Emory University, Atlanta, GA, USA.
  • Tuyishime M; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Falcinelli SD; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • King HAD; Department of Surgery, Duke University Medical Center, Durham, NC, USA.
  • Ke R; UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Mason RD; Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
  • Archin NM; US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
  • Dunham RM; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
  • Safrit JT; Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
  • Jean S; Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
  • Perelson AS; UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Margolis DM; UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Ferrari G; HIV Drug Discovery, ViiV Healthcare, Research Traingle Park, NC, USA.
  • Roederer M; ImmunityBio, Inc., Culver City, CA, USA.
  • Silvestri G; Emory National Primate Research Center, Emory University, Atlanta, GA, USA.
  • Chahroudi A; Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
Nat Med ; 29(10): 2535-2546, 2023 10.
Article em En | MEDLINE | ID: mdl-37783968
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por HIV / Síndrome de Imunodeficiência Adquirida dos Símios / HIV-1 / Vírus da Imunodeficiência Símia Limite: Animals Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Infecções por HIV / Síndrome de Imunodeficiência Adquirida dos Símios / HIV-1 / Vírus da Imunodeficiência Símia Limite: Animals Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos