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

• Published in: PLoS pathogens 2020-09, Vol.16 (9), p.e1008821-e1008821
• Main Authors: Zanoni, Michelle, Palesch, David, Pinacchio, Claudia, Statzu, Maura, Tharp, Gregory K, Paiardini, Mirko, Chahroudi, Ann, Bosinger, Steven E, Yoon, Jack, Cox, Bryan, Silvestri, Guido, Kulpa, Deanna A
• Format: Article
• Language: English
• Subjects: Animals; Antiretroviral agents; Antiretroviral therapy; Biology and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell activation; Cell Proliferation; Cell survival; Cytotoxicity; Gene sequencing; Histocompatibility Antigens Class I - immunology; HIV; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunity, Innate; Immunology; Immunoregulation; Independent study; Infections; Laboratories; Lymphocytes; Lymphocytes T; Macaca; Major histocompatibility complex; Medicine; Medicine and Health Sciences; Pediatrics; Replication; Research and Analysis Methods; Ribonucleic acid; RNA; RNA viruses; Secretome; Software; T cell receptors; T-cell receptor; Transcription; Transcription, Genetic - immunology; Vaccines; Virus Replication - immunology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008821

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.