FOXO1 promotes HIV latency by suppressing ER stress in T cells

Abstract

Quiescence is a hallmark of CD4 + T cells latently infected with 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 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 were for HIV reactivation. Indeed, inhibition of PKR-like endoplasmic reticulum kinase (PERK), 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 between 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.

Epigenomic characterization of latent HIV infection identifies latency regulating transcription factors

“…This TF is associated with a quiescent central memory T cell (Tcm) phenotype, consistent with the hypothesis that cells that adopt a quiescent Tcm phenotype are more prone to latent infection [ 63 ]. Interestingly, a related Forkhead TF, FOXO1, has also recently been reported to promote HIV latency [ 64 , 65 ]. In addition to these known HIV-regulating TFs, several TFs with no known role in HIV transcription were identified by our study, and defining their role in latency will likely lead to the discovery of new mechanisms of transcriptional repression for HIV.…”

A Two-Color Haploid Genetic Screen Identifies Novel Host Factors Involved in HIV-1 Latency

“…The reversal of double-positive cells after sorting may reflect the intrinsically stochastic transcription of HIV-1 ( 84 – 86 ). Latent cell lines are notoriously sensitive to cellular stresses, which cause reactivation ( 87 – 89 ). It is, therefore, possible that the less-stable GFP-positive cells represent cells that are temporarily activated and which slowly revert to a latent state.…”

A histone deacetylase network regulates epigenetic reprogramming and viral silencing in HIV infected cells

“…Our data also support the conclusion that HIV silencing in CD4 T cells is non-random and occurs preferentially in cells with memory T SCM or T CM phenotypes. The preferential silencing of the provirus in these subsets is related at least in part to the transcription factor FOXO1(Roux et al, 2019, p. 1; Vallejo-Gracia et al, 2020, p. 1); preferential silencing in memory T SCM and T CM cells coupled to the longevity and proliferative capacity of these cells is a major factor in the persistence of the latent reservoir. Cells with these phenotypes are preferentially found in clonal expanded cell populations with HIV proviruses(R. Liu et al, 2020; Maldarelli et al, 2014; Murray et al, 2016; Simonetti et al, 2021).…”