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

MHC-I-restricted, virus-specific cytotoxic CD8+ T cells control HIV/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 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 non-productively infected CD4+ T cells harboring integrated, inducible provirus. Finally, we used RNA sequencing and secretome analysis to identify candidate cellular pathways that are involved in the virus-silencing mediated by these CD8+ T cells. This study describes and characterizes a novel 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.