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Nature. 2020 Feb;578(7793):154-159. doi: 10.1038/s41586-020-1946-0. Epub 2020 Jan 22.

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

Author information

1
Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.
2
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
3
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA.
4
International Center for the Advancement of Translational Science, Division of Infectious Diseases, Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
5
University of North Carolina HIV Cure Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
6
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
7
AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
8
NantKwest, Culver City, CA, USA.
9
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
10
Emory + Children's Center for Childhood Infections and Vaccines, Atlanta, GA, USA.
11
Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA. gsilves@emory.edu.
12
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. gsilves@emory.edu.

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.

PMID:
31969705
DOI:
10.1038/s41586-020-1946-0

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