Circadian control of hepatitis B virus replication
Xiaodong Zhuang, Dónall Forde, Senko Tsukuda, Valentina D’Arienzo, Laurent Mailly, James Michael Harris, Peter A. C. Wing, Helene Borrmann, Mirjam Schilling, Andrea Magrì, Claudia Orbegozo Rubio, Robert Maidstone, Mudassar Iqbal, Miguel Garzon, Rosalba Minisini, Mario Pirisi, Sam Butterworth, Peter Balfe, David Ray, Koichi Watashi, Thomas F. Baumert, Jane A. McKeating
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.