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Systemic HIV and SIV latency reversal via non-canonical NF-kappa B signalling in vivo

  1. Author:
    Nixon, Christopher C
    Mavigner, Maud
    Sampey, Gavin C
    Brooks, Alyssa D
    Spagnuolo, Rae Ann
    Irlbeck, David M
    Mattingly, Cameron
    Ho, Phong T
    Schoof, Nils
    Cammon, Corinne G
    Tharp, Greg K
    Kanke, Matthew
    Wang, Zhang
    Cleary, Rachel A
    Upadhyay, Amit A
    De, Chandrav
    Wills, Saintedym R
    Falcinelli, Shane D
    Galardi, Cristin
    Walum, Hasse
    Schramm, Nathaniel J
    Deutsch, Jennifer
    Lifson,Jeffrey
    Fennessey,Christine
    Keele,Brandon
    Jean, Sherrie
    Maguire, Sean
    Liao, Baolin
    Browne, Edward P
    Ferris, Robert G
    Brehm, Jessica H
    Favre, David
    Vanderford, Thomas H
    Bosinger, Steven E
    Jones, Corbin D
    Routy, Jean-Pierre
    Archin, Nancie M
    Margolis, David M
    Wahl, Angela
    Dunham, Richard M
    Silvestri, Guido
    Chahroudi, Ann
    Garcia, J Victor

  2. Author Address

    International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA., UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Qura Therapeutics, Chapel Hill, NC, USA., HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, NC, USA., Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA., Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., GlaxoSmithKline Research and Development, Collegeville, PA, USA., Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Department of Infectious Diseases, Guangzhou Eighth People 39;s Hospital, Guangzhou Medical University, Guangzhou, China., Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA., Chronic Viral Infection Service, McGill University Health Centre, Montreal, Quebec, Canada., Division of Hematology, McGill University Health Centre, Montreal, Quebec, Canada., Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com., Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com., UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com., Qura Therapeutics, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com., HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, NC, USA. richard.m.dunham@viivhealthcare.com., Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. ann.m.chahroudi@emory.edu., Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA. ann.m.chahroudi@emory.edu., Emory + Children 39;s Center for Childhood Infections and Vaccines, Atlanta, GA, USA. ann.m.chahroudi@emory.edu., International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu., Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu., Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.,
    1. Year: 2020
    2. Date: Jan 22
    3. Epub Date: 2020 01 22
  2. Journal: Nature
  4. Type of Article: Article
  5. ISSN: 0028-0836
  1. Abstract:

    Activation of the non-canonical NF-kappa B signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of antiretroviral-therapy-treated humanized mice and rhesus macaques. Long-lasting, latently infected resting CD4(+) T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir(1). Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect(2-9). Here we show that activation of the non-canonical NF-kappa B signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4(+) T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.

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  2. DOI: 10.1038/s41586-020-1951-3
  3. PMID: 31969707
  4. View record in Web of Science®
  5. WOS: WOS:000508801100012
  6. PII : 10.1038/s41586-020-1951-3

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  1. Fiscal Year: FY2019-2020
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