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.

静止是潜伏感染人类免疫缺陷病毒 1 (HIV-1) 的 CD4 ⁺ T 细胞的标志。虽然逆转这种静止状态是从培养物中的 T 细胞中重新激活潜在 HIV 的有效方法，但它可能会导致患者出现有害的细胞因子失调。作为 T 细胞静止的关键调节因子，FOXO1 可以促进潜伏期并抑制有效的 HIV 感染。我们报告说，在静息 T 细胞中，FOXO1 抑制会损害自噬并诱导内质网 (ER) 应激，从而激活两个相关的转录因子：激活转录因子 4 (ATF4) 和激活 T 细胞核因子 (NFAT)。这两个因素都与 HIV 染色质相关，并且是 HIV 重新激活所必需的。事实上，抑制蛋白激酶 R 样 ER 激酶（一种可以介导 ATF4 诱导的 ER 应激传感器）和钙调神经磷酸酶（NFAT 的钙依赖性调节剂）可协同抑制 FOXO1 抑制引起的 HIV 再激活。因此，我们的研究揭示了 FOXO1、内质网应激和 HIV 感染之间的联系，可用于治疗性地选择性逆转 T 细胞静止并减少潜伏病毒库的大小。