Innate, non-cytolytic CD8(+)T cell-mediated suppression of HIV replication by MHC-independent inhibition of virus transcription

• Type of Material: Article
• Authors: Michelle Zanoni, Emory University; David Palesch, Emory University; Claudia Pinacchio, Emory University; Maura Statzu, Emory University; Gregory K. Tharp, Emory University; Mirko Paiardini, Emory University; Ann Chahroudi, Emory University; Steven Bosinger, Emory University; Jack Yoon, Emory University; Bryan Cox, Emory University; Guido Silvestri, Emory University; Deanna Kulpa, Emory University
• Language: English
• Date: 2020-09-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2020 Zanoni et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1008821
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 16
• Issue: 9
• Start Page: e1008821
• End Page: e1008821
• Grant/Funding Information: Research reported in this publication was also supported by the Center for AIDS Research (CFAR) at Emory University #P30AI050409 (GS).; MZ was supported by a fellowship from the Brazil National Council of Technological and Scientific Development (CNPQ)/ Science without Borders, and by a fellowship from Emory AIDS Vaccine 200 (AV200).; This work was funded by NIH grant #1R01AI125064 (GS) and #1R01AI143414-01 (DAK).
• Keywords: Parasitology; VIREMIA; IMMUNODEFICIENCY-VIRUS; Microbiology; TYPE-1; RESERVOIR; Life Sciences & Biomedicine; INFECTION; LYMPHOCYTES; IMMUNE-RESPONSES; T-CELLS; HLA; Virology; DEPLETION; Science & Technology
• Research Categories: Biology, Parasitology; Health Sciences, Immunology; Biology, Microbiology

Abstract

MHC-I-restricted, virus-specific cytotoxic CD8+ T cells (CTLs) may control human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication via the recognition and killing of productively infected CD4+ T cells. Several studies in SIV-infected macaques suggest that CD8+ T cells may also decrease virus production by suppressing viral transcription. Here, we show that non-HIV-specific, TCR-activated non-cytolytic CD8+ T cells suppress HIV transcription via a virus- and MHC-independent immunoregulatory mechanism that modulates CD4+ T cell proliferation and activation. We also demonstrate that this CD8+ T cell-mediated effect promotes the survival of infected CD4+ T cells harboring integrated, inducible virus. Finally, we used RNA sequencing and secretome analyses to identify candidate cellular pathways that are involved in the virus-silencing mediated by these CD8+ T cells. This study characterizes a previously undescribed mechanism of immune-mediated HIV silencing that may be involved in the establishment and maintenance of the reservoir under antiretroviral therapy and therefore represent a major obstacle to HIV eradication.