FOXO1 promotes HIV latency by suppressing ER stress in T cells

Nat Microbiol. 2020 Sep;5(9):1144-1157. doi: 10.1038/s41564-020-0742-9. Epub 2020 Jun 15.


Quiescence is a hallmark of CD4+ T cells latently infected with human immunodeficiency virus 1 (HIV-1). While reversing this quiescence is an effective approach to reactivate latent HIV from T cells in culture, it can cause deleterious cytokine dysregulation in patients. As a key regulator of T-cell quiescence, FOXO1 promotes latency and suppresses productive HIV infection. We report that, in resting T cells, FOXO1 inhibition impaired autophagy and induced endoplasmic reticulum (ER) stress, thereby activating two associated transcription factors: activating transcription factor 4 (ATF4) and nuclear factor of activated T cells (NFAT). Both factors associate with HIV chromatin and are necessary for HIV reactivation. Indeed, inhibition of protein kinase R-like ER kinase, an ER stress sensor that can mediate the induction of ATF4, and calcineurin, a calcium-dependent regulator of NFAT, synergistically suppressed HIV reactivation induced by FOXO1 inhibition. Thus, our studies uncover a link of FOXO1, ER stress and HIV infection that could be therapeutically exploited to selectively reverse T-cell quiescence and reduce the size of the latent viral reservoir.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Endoplasmic Reticulum Stress / drug effects*
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / metabolism*
  • Forkhead Box Protein O1 / pharmacology*
  • Gene Knockdown Techniques
  • HIV Infections / virology
  • HIV-1 / drug effects*
  • Humans
  • K562 Cells
  • Virus Activation / drug effects*
  • Virus Latency / drug effects*


  • ATF4 protein, human
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Activating Transcription Factor 4