Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells

Julia Bergild McBrien, Maud Mavigner, Lavinia Franchitti, S. Abigail Smith, Erick White, Gregory K. Tharp, Hasse Walum, Kathleen Busman-Sahay, Christian R. Aguilera-Sandoval, William O. Thayer, Rae Ann Spagnuolo, Martina Kovarova, Angela Wahl, Barbara Cervasi, David M. Margolis, Thomas H. Vanderford, Diane G. Carnathan, Mirko Paiardini, Jeffrey D. Lifson, John H. Lee, Jeffrey T. Safrit, Steven E. Bosinger, Jacob D. Estes, Cynthia A. Derdeyn, J. Victor Garcia, Deanna A. Kulpa, Ann Chahroudi and Guido Silvestri ()
Additional contact information
Julia Bergild McBrien: Emory University
Maud Mavigner: Emory University School of Medicine
Lavinia Franchitti: Emory University
S. Abigail Smith: Emory University
Erick White: Emory University
Gregory K. Tharp: Emory University
Hasse Walum: Emory University
Kathleen Busman-Sahay: Oregon Health & Science University
Christian R. Aguilera-Sandoval: University of North Carolina at Chapel Hill
William O. Thayer: University of North Carolina at Chapel Hill
Rae Ann Spagnuolo: University of North Carolina at Chapel Hill
Martina Kovarova: University of North Carolina at Chapel Hill
Angela Wahl: University of North Carolina at Chapel Hill
Barbara Cervasi: Emory University
David M. Margolis: University of North Carolina at Chapel Hill
Thomas H. Vanderford: Emory University
Diane G. Carnathan: Emory University
Mirko Paiardini: Emory University
Jeffrey D. Lifson: Frederick National Laboratory for Cancer Research
John H. Lee: NantKwest
Jeffrey T. Safrit: NantKwest
Steven E. Bosinger: Emory University
Jacob D. Estes: Oregon Health & Science University
Cynthia A. Derdeyn: Emory University
J. Victor Garcia: University of North Carolina at Chapel Hill
Deanna A. Kulpa: Emory University
Ann Chahroudi: Emory University School of Medicine
Guido Silvestri: Emory University

Nature, 2020, vol. 578, issue 7793, 154-159

Abstract: Abstract Human immunodeficiency virus (HIV) persists indefinitely in individuals with HIV who receive antiretroviral therapy (ART) owing to a reservoir of latently infected cells that contain replication-competent virus1–4. Here, to better understand the mechanisms responsible for latency persistence and reversal, we used the interleukin-15 superagonist N-803 in conjunction with the depletion of CD8+ lymphocytes in ART-treated macaques infected with simian immunodeficiency virus (SIV). Although N-803 alone did not reactivate virus production, its administration after the depletion of CD8+ lymphocytes in conjunction with ART treatment induced robust and persistent reactivation of the virus in vivo. We found viraemia of more than 60 copies per ml in all macaques (n = 14; 100%) and in 41 out of a total of 56 samples (73.2%) that were collected each week after N-803 administration. Notably, concordant results were obtained in ART-treated HIV-infected humanized mice. In addition, we observed that co-culture with CD8+ T cells blocked the in vitro latency-reversing effect of N-803 on primary human CD4+ T cells that were latently infected with HIV. These results advance our understanding of the mechanisms responsible for latency reversal and lentivirus reactivation during ART-suppressed infection.

Date: 2020
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DOI: 10.1038/s41586-020-1946-0

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