PLoS Pathogens (Sep 2020)

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 Cox,
  • Guido Silvestri,
  • Deanna A Kulpa

DOI
https://doi.org/10.1371/journal.ppat.1008821
Journal volume & issue
Vol. 16, no. 9
p. e1008821

Abstract

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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.