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

Christopher C. Nixon, Maud Mavigner, Gavin C. Sampey, Alyssa D. Brooks, Rae Ann Spagnuolo, David M. Irlbeck, Cameron Mattingly, Phong T. Ho, Nils Schoof, Corinne G. Cammon, Greg K. Tharp, Matthew Kanke, Zhang Wang, Rachel A. Cleary, Amit A. Upadhyay, Chandrav De, Saintedym R. Wills, Shane D. Falcinelli, Cristin Galardi, Hasse Walum, Nathaniel J. Schramm, Jennifer Deutsch, Jeffrey D. Lifson, Christine M. Fennessey, Brandon F. Keele, Sherrie Jean, Sean Maguire, Baolin Liao, Edward P. Browne, Robert G. Ferris, Jessica H. Brehm, David Favre, Thomas H. Vanderford, Steven E. Bosinger, Corbin D. Jones, Jean-Pierre Routy, Nancie M. Archin, David M. Margolis, Angela Wahl, Richard M. Dunham (), Guido Silvestri, Ann Chahroudi () and J. Victor Garcia ()
Additional contact information
Christopher C. Nixon: University of North Carolina at Chapel Hill
Maud Mavigner: Emory University School of Medicine
Gavin C. Sampey: University of North Carolina at Chapel Hill
Alyssa D. Brooks: Emory University School of Medicine
Rae Ann Spagnuolo: University of North Carolina at Chapel Hill
David M. Irlbeck: Qura Therapeutics
Cameron Mattingly: Emory University School of Medicine
Phong T. Ho: University of North Carolina at Chapel Hill
Nils Schoof: Emory University School of Medicine
Corinne G. Cammon: University of North Carolina at Chapel Hill
Greg K. Tharp: Emory University
Matthew Kanke: University of North Carolina at Chapel Hill
Zhang Wang: GlaxoSmithKline Research and Development
Rachel A. Cleary: University of North Carolina at Chapel Hill
Amit A. Upadhyay: Emory University
Chandrav De: University of North Carolina at Chapel Hill
Saintedym R. Wills: University of North Carolina at Chapel Hill
Shane D. Falcinelli: University of North Carolina at Chapel Hill
Cristin Galardi: Qura Therapeutics
Hasse Walum: Emory University
Nathaniel J. Schramm: University of North Carolina at Chapel Hill
Jennifer Deutsch: GlaxoSmithKline Research and Development
Jeffrey D. Lifson: Frederick National Laboratory for Cancer Research
Christine M. Fennessey: Frederick National Laboratory for Cancer Research
Brandon F. Keele: Frederick National Laboratory for Cancer Research
Sherrie Jean: Emory University
Sean Maguire: GlaxoSmithKline Research and Development
Baolin Liao: University of North Carolina at Chapel Hill
Edward P. Browne: University of North Carolina at Chapel Hill
Robert G. Ferris: Qura Therapeutics
Jessica H. Brehm: Qura Therapeutics
David Favre: Qura Therapeutics
Thomas H. Vanderford: Emory University
Steven E. Bosinger: Emory University
Corbin D. Jones: University of North Carolina at Chapel Hill
Jean-Pierre Routy: McGill University Health Centre
Nancie M. Archin: University of North Carolina at Chapel Hill
David M. Margolis: University of North Carolina at Chapel Hill
Angela Wahl: University of North Carolina at Chapel Hill
Richard M. Dunham: University of North Carolina at Chapel Hill
Guido Silvestri: Emory University
Ann Chahroudi: Emory University School of Medicine
J. Victor Garcia: University of North Carolina at Chapel Hill

Nature, 2020, vol. 578, issue 7793, 160-165

Abstract: Abstract 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 reservoir1. 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 effect2–9. Here we show that activation of the non-canonical NF-κB 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.

Date: 2020
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DOI: 10.1038/s41586-020-1951-3

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