Targeting the circadian clock to restore hepatitis B T-cell immunity

Circadian rhythms regulate changes in physiological and metabolic processes which allow organisms on earth to respond to daily environmental demands and pathogenic exposure. Host innate and adaptive immune responses are circadian regulated and influence susceptibility to viral infection and response to vaccines. In recent years, scientists have discovered the genetic machinery that underpins the daily cycling of the circadian clock that operates in individual cells. Furthermore, scientists uncovered communications between circadian clocks of different cell types within an organ, and that genetically perturbing the clock in the hepatocytes can impact the clocks in their neighbouring immune cells. Therefore, there is reason to believe that the circadian clock controls immunity within the liver which is essential for viral protection.

Hepatitis B virus (HBV) only infects the human liver and remains a major health problem with >270 million chronic infections and 880,000 deaths/year worldwide from liver disease including cirrhosis and cancer. Current antivirals reduce the viral burden but are not curative and do not remove the risk of liver cancer. Chronic hepatitis B is associated with poor anti-viral T-cell immunity that fails to control viral replication. Therefore, curative treatments are desperately needed, and understanding what causes these T-cell defects could aid the design and evaluation of curative therapies.

We recently discovered a disruption of clock genes in the liver of HBV patients, which I hypothesise contributes to the poor T-cell response in the infected liver. Importantly, our recent data suggest that manipulation of circadian pathways by drugs can enhance the function of HBV-specific T-cells in CHB patients. Therefore by studying how the circadian system regulates T-cell immunity in the infected liver and how the time of day affects HBV vaccine efficacy, we will identify novel therapeutic opportunities for T-cell restoration and improve the efficacy of HBV therapeutic vaccines. In a broader context, knowledge of the communication of clocks between tissue and local immunity will be applicable to many other pathogens.

The circadian clock operates in most cells including T-cells. The immune response to pathogens is influenced by the local tissue microenvironment. However, how immune cells and parenchymal cells communicate their clocks under physiological and pathological conditions is not fully understood. We discovered a perturbation of clock gene expression within the liver of HBV-infected mice and chronic hepatitis B (CHB) patients, presenting a unique pathophysiological condition to dissect the circadian regulation between the liver and resident immune cells. Our team will first establish whether the liver-resident CD8+ T-cell clock is influenced by the hepatic clock and how HBV infection impacts this interaction by transcriptome profiling of liver resident T-cells derived from circadian entrained mice. Secondly, a library of fully characterized circadian modulators will be evaluated for their ability to restore dysfunctional CD8+ T-cells derived from CHB patients. Finally, we will evaluate the time-of-day effect on HBV therapeutic vaccine efficacy in HBV-infected mice and test circadian modulators as potential adjuvants to improve the vaccine immune response. These studies will reveal mechanistic interactions between the hepatic circadian clock and HBV T-cell immunity and identify novel approaches to contribute to HBV functional cure.