Circadian control of hepatitis B virus replication

Xiaodong Zhuang (), Donall Forde, Senko Tsukuda, Valentina D’Arienzo, Laurent Mailly, James M. Harris, Peter A. C. Wing, Helene Borrmann, Mirjam Schilling, Andrea Magri, Claudia Orbegozo Rubio, Robert J. Maidstone, Mudassar Iqbal, Miguel Garzon, Rosalba Minisini, Mario Pirisi, Sam Butterworth, Peter Balfe, David W. Ray, Koichi Watashi, Thomas F. Baumert and Jane A. McKeating ()
Additional contact information
Xiaodong Zhuang: University of Oxford
Donall Forde: University of Oxford
Senko Tsukuda: University of Oxford
Valentina D’Arienzo: University of Oxford
Laurent Mailly: UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques
James M. Harris: University of Oxford
Peter A. C. Wing: University of Oxford
Helene Borrmann: University of Oxford
Mirjam Schilling: University of Oxford
Andrea Magri: University of Oxford
Claudia Orbegozo Rubio: University of Oxford
Robert J. Maidstone: John Radcliffe Hospital
Mudassar Iqbal: University of Manchester
Miguel Garzon: University of Manchester
Rosalba Minisini: Università del Piemonte Orientale
Mario Pirisi: Università del Piemonte Orientale
Sam Butterworth: University of Manchester
Peter Balfe: University of Oxford
David W. Ray: John Radcliffe Hospital
Koichi Watashi: National Institute of Infectious Diseases
Thomas F. Baumert: UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques
Jane A. McKeating: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses.

Date: 2021
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DOI: 10.1038/s41467-021-21821-0

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