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Circadian control of hepatitis B virus replication

Author

Listed:
  • Xiaodong Zhuang

    (University of Oxford)

  • Donall Forde

    (University of Oxford)

  • Senko Tsukuda

    (University of Oxford
    National Institute of Infectious Diseases
    RIKEN Cluster for Pioneering Research)

  • 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
    University of Oxford)

  • 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
    University of Oxford)

  • Koichi Watashi

    (National Institute of Infectious Diseases
    RIKEN Cluster for Pioneering Research
    Kyoto University)

  • Thomas F. Baumert

    (UMR-S1110, Institut de Recherche sur les Maladies Virales et Hépatiques
    Hopitaux Universitaire de Strasbourg, Strasbourg and Institut Universitaire de France)

  • Jane A. McKeating

    (University of Oxford)

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.

Suggested Citation

  • 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 , 2021. "Circadian control of hepatitis B virus replication," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21821-0
    DOI: 10.1038/s41467-021-21821-0
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    Cited by:

    1. María José Viana Cleves & Gerardo Barbosa Castillo & Andrés Rolando Ciro Gómez & Édgar Solano González, 2022. "Líneas estructurales para la Fuerza Pública: medioambiente e inteligencia militar," Books, Universidad Externado de Colombia, Facultad de Derecho, number 1330.
    2. Atish Mukherji & Frank Jühling & Yogy Simanjuntak & Emilie Crouchet & Fabio Zompo & Yuji Teraoka & Alexandre Haller & Philippe Baltzinger & Soumith Paritala & Fahmida Rasha & Naoto Fujiwara & Cloé Gad, 2024. "An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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