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.

Diurnal Variation in SARS-CoV-2 PCR Test Results: Test Accuracy May Vary by Time of Day

“…The potential impact of time of day on diagnostic test accuracy, however, has not been examined previously. There is considerable evidence for circadian regulation of the immune system that could lead to daily patterns of viral shedding and therefore to a diurnal variation in the viral titer in biological tissues (Cermakian et al, 2013;Edgar et al, 2016;Scheiermann et al, 2018;Zhuang et al, 2021a). Anecdotal reports suggest that symptoms of COVID-19 vary by time of day, and recent preliminary in vitro data identified circadian effects on viral infection and replication (Zhuang et al, 2021b).…”

Circadian Rhythm Modulation of Microbes During Health and Infection

“…Further, the protective effect was due to Rev-Erbα-mediated ccl2 repression at the start of the active phase, leading to reduced recruitment of inflammatory cells, and thus reduced disease severity. Similarly, Rev-Erbα agonists repressed the replication of hepatitis B and C viruses (HBV, Zhuang et al, 2021;HCV, Zhuang et al, 2019) and human immunodeficiency virus (HIV, Chang et al, 2018;Borrmann et al, 2020), whereas Bmal1 expression promoted viral replication. It is noteworthy that Bmal1 is negatively regulated by Rev-Erbα.…”

“…Therapies targeting the circadian clock have shown promise in controlling bacterial and viral infection. SR9009, a REV-ERB agonist, which suppresses Bmal1, has successfully inhibited viral entry and replication of HCV (Zhuang et al, 2019), HBV (Zhuang et al, 2021), and HIV-1 (Borrmann et al, 2020). Likewise, SR8278, a REV-ERB antagonist, which represses Rev-erbα and promotes Bmal1 expression, has rendered mice more susceptible to VSV infection when infected at ZT12, compared to the more protected mice infected at ZT12 without REV-ERB antagonist treatment (Gagnidze et al, 2016).…”

COVID-19: Sleep, Circadian Rhythms and Immunity – Repurposing Drugs and Chronotherapeutics for SARS-CoV-2

“…It has been established categorically that the circadian rhythms can regulate our innate and adaptive immune response, modulate viral replication within the host cells, coordinate physiological processes, and often determine the severity of many illnesses (Zhuang et al, 2017;Haspel et al, 2020). Prior evidence indicates that if the circadian system is disrupted, the vulnerability of host cells toward influenza and herpes virus increases (Edgar et al, 2016;Mazzoccoli et al, 2020;Zhuang et al, 2021). It may seem counterintuitive but the truth is occurrences of circadian disruption and disturbances in sleep had been more frequent during the pandemic despite social confinement (Morin et al, 2020).…”