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

• Type of Material: Article
• Authors: Julia Bergild McBrien, Emory University; Maud Mavigner, Emory University; Lavinia Franchitti, Emory University; S. Abigail Smith, Emory University; Erick White, Emory University; Gregory K. Tharp, Emory University; Hasse Walum, Emory University; Kathleen Busman-Suhay, Oregon Health and Science University; Christian R. Aguilera-Sandoval, University of North Carolina; William O. Thayer, University of North Carolina; Rae Ann Spagnuolo, University of North Carolina; Martina Kovarova, University of North Carolina; Angela Wahl, University of North Carolina; Barbara Cervasi, Emory University; David M. Margolis, University of North Carolina; Thomas 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 Bosinger, Emory University; Jacob D. Estes, Oregon Health and Science University; Cynthia Derdeyn, Emory University; J. Victor Garcia, University of North Carolina; Deanna Kulpa, Emory University; Ann Chahroudi, Emory University; Guido Silvestri, Emory University
• Language: English
• Date: 2020-01-22
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): http://dx.doi.org/10.1038/s41586-020-1946-0
• Title of Journal or Parent Work: NATURE
• Volume: 578
• Issue: 7793
• Start Page: 154
• End Page: +
• Grant/Funding Information: This work was supported by NIH grants R01-AI125064 and UM1-AI124436 (to G.S. and A.C.); R01-AI143414 (to G.S. and D.A.K); R01-MH108179 and R01-AI111899 (to J.V.G.); UM1-AI126619 (to D.M.M.); R01-AI123010 (to A.W.); P30 AI050409 (Emory Center for AIDS Research); P51 OD011092 (Oregon National Primate Research Center base grant); the National Institutes of Health’s Office of the Director, Office of Research Infrastructure Programs P51OD011132 (Yerkes National Primate Research Center base grant); and supported in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contracts HHSN261200800001E and 75N91019D00024 (J.D.L).
• Keywords: LATENT RESERVOIR; Science & Technology - Other Topics; INFECTION; ANTIRETROVIRAL THERAPY; SIGNATURES; DISULFIRAM; PLASMA; BREAKTHROUGH; REPLICATION; Multidisciplinary Sciences; SUPPRESSION; EXPRESSION; Science & Technology

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.