Circadian control of hepatitis B virus replication

Area of Science:

• Hepatology
• Virology
• Chronobiology

Background:

• Chronic hepatitis B virus (HBV) infection lacks curative therapies, with viral cccDNA persistence being a major hurdle.
• Circadian regulators BMAL1/CLOCK and REV-ERB control liver gene expression, but their role in HBV replication is unexplored.

Purpose of the Study:

• To investigate the role of circadian factors BMAL1 and REV-ERB in HBV replication.
• To explore the therapeutic potential of targeting these circadian regulators for HBV infection.

Main Methods:

• Established a circadian cycling liver cell model.
• Investigated the direct regulation of NTCP-dependent HBV entry by REV-ERB.
• Assessed the impact of pharmacological REV-ERB activation and BMAL1 inhibition on HBV infection in vitro and in human liver chimeric mice.

Main Results:

• REV-ERB directly regulates hepatitis B and delta virus entry via NTCP.
• Pharmacological REV-ERB activation inhibited HBV infection in vitro and in vivo.
• BMAL1 binds HBV genomes, enhancing viral promoter activity; its inhibition reduced viral RNA and particle secretion.

Conclusions:

• Circadian factors BMAL1 and REV-ERB play significant roles in regulating HBV replication.
• Targeting REV-ERB and BMAL1 presents a potential novel therapeutic strategy for chronic HBV infection.
• The role of BMAL1 in regulating hepadnaviruses is evolutionarily conserved.