Molecular components of the circadian clock regulate HIV-1 replication

Helene Borrmann; Görkem Ulkar; Anna E Kliszczak; Dini Ismed; Mirjam Schilling; Andrea Magri; James M Harris; Peter Balfe; Sridhar Vasudevan; Persephone Borrow; Xiaodong Zhuang; Jane A McKeating

doi:10.1016/j.isci.2023.107007

Molecular components of the circadian clock regulate HIV-1 replication

iScience. 2023 May 29;26(7):107007. doi: 10.1016/j.isci.2023.107007. eCollection 2023 Jul 21.

Authors

Affiliations

¹ Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
² Department of Pharmacology, University of Oxford, Oxford, UK.
³ Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK.

Abstract

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 Bmal1 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.

Keywords: Bioinformatics; Biological sciences; Molecular biology; Virology.

Grants and funding

UM1 AI164567/AI/NIAID NIH HHS/United States