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
Affiliations
Helene Borrmann
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Görkem Ulkar
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Anna E. Kliszczak
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Dini Ismed
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Mirjam Schilling
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Andrea Magri
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
James M. Harris
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Peter Balfe
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Sridhar Vasudevan
Department of Pharmacology, University of Oxford, Oxford, UK
Persephone Borrow
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Xiaodong Zhuang
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Corresponding author
Jane A. McKeating
Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK; Corresponding author
Summary: 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.
