Plasek Hegde Leah M, Gunawardane Lalith S, Niazi Farshad, Mbonye Uri, Leskov Konstantin, Perez Gani, Dobrowolski Curtis, Shukla Meenakshi, Nutt William S, Karn Jonathan, Valadkhan Saba
Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA.
Nat Microbiol. 2025 Sep 26. doi: 10.1038/s41564-025-02128-y.
Human immunodeficiency virus (HIV) persists in infected individuals despite effective antiretroviral therapy due to the rapid establishment of latent reservoirs, mainly composed of quiescent memory CD4+ T cells. The mechanisms governing latent reservoir formation remain poorly understood. Here, using single-cell RNA-seq and functional studies in human primary CD4+ T cell models, we show that HIV infection with reporter constructs and laboratory and patient-derived strains triggers transcriptomic remodelling, activating the p53 pathway and a quiescence programme mediated by Krüppel-like factor 2 (KLF2), a key quiescence regulator. Loss- and gain-of-function studies, including unbiased shRNA screens and confirmatory studies in CD4+ T cells from HIV+ donors, demonstrate that HIV infection drives KLF2 and p53 signalling, which downregulate MYC and proliferation pathways, resulting in proviral transcriptional silencing. This enhances latent reservoir formation in T cells, ensuring viral persistence. These findings present a mechanism for forming the latent HIV reservoir and broaden the repertoire of strategies through which viruses control host cells to their advantage.
尽管有有效的抗逆转录病毒疗法，但由于潜伏库的迅速建立，人类免疫缺陷病毒（HIV）仍会在受感染个体中持续存在，这些潜伏库主要由静止的记忆CD4+T细胞组成。目前，对于潜伏库形成的机制仍知之甚少。在此，我们通过在人类原代CD4+T细胞模型中进行单细胞RNA测序和功能研究，发现携带报告基因构建体以及实验室和患者来源毒株的HIV感染会引发转录组重塑，激活p53信号通路以及由关键静止调节因子Krüppel样因子2（KLF2）介导的静止程序。功能缺失和功能获得研究，包括无偏倚的短发夹RNA筛选以及对HIV阳性供体的CD4+T细胞进行的验证性研究，表明HIV感染会驱动KLF2和p53信号传导，从而下调MYC和增殖信号通路，导致前病毒转录沉默。这增强了T细胞中潜伏库的形成，确保了病毒的持续存在。这些发现揭示了潜伏HIV库形成的机制，并拓宽了病毒利用自身优势控制宿主细胞的策略范围。
