@article{1e9ba26a08c04fc99656d4d14e02acb8,
title = "Circadian control of hepatitis B virus replication",
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.",
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",
author = "Xiaodong Zhuang and Donall Forde and Senko Tsukuda and Valentina D{\textquoteright}Arienzo and Laurent Mailly and Harris, {James M.} and Wing, {Peter A.C.} and Helene Borrmann and Mirjam Schilling and Andrea Magri and Rubio, {Claudia Orbegozo} and Maidstone, {Robert J.} and Mudassar Iqbal and Miguel Garzon and Rosalba Minisini and Mario Pirisi and Sam Butterworth and Peter Balfe and Ray, {David W.} and Koichi Watashi and Baumert, {Thomas F.} and McKeating, {Jane A.}",
note = "Funding Information: We wish to thank: Prof U Protzer (TUM, Germany) for providing HepG2-pEpi cells and HepaRG cells; Dr B Grimaldi (University of Genoa, Italy) for Lenti-shRev-Erbα constructs; Dr X Qin (Anhui University, Hefei, China) for Cry1 promoter construct, Bmal1 and Clock expression plasmids; Prof S Urban (University of Heidelberg, Germany) for Myrcludex B; Nicolas Brignon for technical help with animal work; Dina Kremsdorf for providing HBV for mouse infection studies and Alvina Lai for discussions on this project. This work was funded by Wellcome award IA 200838/Z/16/Z (JAM); Wellcome Institutional Strategic Support Fund 0005025 (JAM); MRC project grant MR/R022011/1 (JAM); MRC program grant MR/P023576/1 (DR); Wellcome 107849/A/15/Z (DR); Japan Agency for Medical Research and Development (AMED) J-PRIDE, JP19fm0208019j0003 (K.W.), AMED Program on the Innovative Development and the Application of New Drugs for Hepatitis B, JP19fk0310114j0003 (K.W.), and AMED Program for Basic and Clinical Research on Hepatitis, JP19fk0210036j0002 (K.W.). ARC, Paris (TheraHCC2 IHUARC2019 to T.F.B.), the European Union (EU H2020-667273-HEPCAR to J.A.M. and T.F.B., ANRS; LabEx HepSys and Inserm Plan Cancer (T.F.B.). Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = mar,
day = "12",
doi = "10.1038/s41467-021-21821-0",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}
