Borrmann Helene, Ulkar Görkem, Kliszczak Anna E, Ismed Dini, Schilling Mirjam, Magri Andrea, Harris James M, Balfe Peter, Vasudevan Sridhar, Borrow Persephone, Zhuang Xiaodong, McKeating Jane A
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Department of Pharmacology, University of Oxford, Oxford, UK.
iScience. 2023 May 29;26(7):107007. doi: 10.1016/j.isci.2023.107007. eCollection 2023 Jul 21.
Human immunodeficiency virus 1 (HIV-1) causes major health burdens worldwide and still lacks curative therapies and vaccines. Circadian rhythms are endogenous daily oscillations that coordinate an organism's response to its environment and invading pathogens. Peripheral viral loads of HIV-1 infected patients show diurnal variation; however, the underlying mechanisms remain unknown. Here, we demonstrate a role for the cell-intrinsic clock to regulate rhythmic HIV-1 replication in circadian-synchronized systems. Silencing the circadian activator abolishes this phenotype, and we observe BMAL1 binding to the HIV-1 promoter. Importantly, we show differential binding of the nuclear receptors REV-ERB and ROR to the HIV-long terminal repeat at different circadian times, demonstrating a dynamic interplay in time-of-day regulation of HIV-1 transcription. Bioinformatic analysis shows circadian regulation of host factors that control HIV-1 replication, providing an additional mechanism for rhythmic viral replication. This study increases our understanding of the circadian regulation of HIV-1, which can ultimately inform new therapies.
人类免疫缺陷病毒1型（HIV-1）在全球范围内造成了重大的健康负担，目前仍然缺乏治愈性疗法和疫苗。昼夜节律是一种内源性的每日振荡，它协调生物体对其环境和入侵病原体的反应。HIV-1感染患者的外周病毒载量呈现昼夜变化；然而，其潜在机制仍然未知。在这里，我们证明了细胞内生物钟在昼夜节律同步系统中对HIV-1节律性复制的调节作用。沉默昼夜激活因子可消除这种表型，并且我们观察到BMAL1与HIV-1启动子结合。重要的是，我们发现在不同的昼夜时间，核受体REV-ERB和ROR与HIV长末端重复序列的结合存在差异，这表明在HIV-1转录的昼夜调节中存在动态相互作用。生物信息学分析表明，控制HIV-1复制的宿主因子存在昼夜节律调节，这为节律性病毒复制提供了另一种机制。这项研究增进了我们对HIV-1昼夜调节的理解，最终可为新疗法提供依据。
