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 WatashiThomas F. Baumert, Jane A. McKeating

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1658
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 12 Mar 2021

Keywords

  • Animals
  • Biological Clocks/drug effects
  • Circadian Rhythm/genetics
  • DNA, Circular
  • DNA, Viral/metabolism
  • Gene Expression Regulation
  • Genome, Viral
  • Hep G2 Cells
  • Hepatitis B virus/genetics
  • Hepatitis B, Chronic/genetics
  • Hepatitis B/virology
  • Hepatocytes/metabolism
  • Host-Pathogen Interactions/genetics
  • Humans
  • Liver/metabolism
  • Mice
  • Organic Anion Transporters, Sodium-Dependent/metabolism
  • Promoter Regions, Genetic
  • Symporters/metabolism
  • Transcriptome
  • Virion/metabolism
  • Virus Internalization
  • Virus Replication/physiology

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