Innate, non-cytolytic CD8+ T cell-mediated suppression of HIV replication by MHC-independent inhibition of virus transcription
Michelle Zanoni, David Palesch, Claudia Pinacchio, Maura Statzu, Gregory K. Tharp, Mirko Paiardini, Ann Chahroudi, Steven E. Bosinger, Jack Yoon, Bryan D. Cox, Guido Silvestri, Deanna A. Kulpa
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.