Professor of Molecular Virology
Hypoxic and circadian regulation of viruses
Our research focuses on understanding the role of oxygen and circadian signalling pathways in the regulation of virus infection and how this influences viral tropism and disease pathogenesis. Chronic viral infection of the liver is a global health problem, with over 500 million individuals infected with hepatitis B (HBV) or C (HCV) viruses that cause progressive liver disease that can develop into hepatocellular carcinoma. The low oxygen environment of the liver promotes HBV replication via hypoxia inducible transcription factor (HIFs) binding the viral genome and activating transcription. We are actively studying the role of other oxygenases in regulating host susceptibility to virus infection.
Oxygen tension can vary at different anatomical sites and this can impact viral replication and tropism. For example, immune cells encounter variable oxygen tensions as they migrate from the periphery into tissue and are a major reservoir for HIV infection. We found that HIFs supress HIV transcription and a low oxygen environment favors viral latency. Recent studies during the COVID-19 pandemic highlight a role for HIFs and HIF-mimetic drugs to supress SARS-CoV-2 replication in lung epithelial cells. Our research shows that HIFs can act as a rheostat to determine viral replication and tropism. Pharmaceutical agents that modulate HIF activity provide new therapeutic targets for treating viral infections and associated pathologies.
The circadian clock controls many aspects of mammalian physiology and orchestrates the daily oscillations of biological processes and behavior. An endogenous central clock in the brain synchronizes with clocks in peripheral tissues and regulates our immune system and outcome to viral infections. Our laboratory discovered a role for the circadian transcriptional activator BMAL1 in the regulation of HBV and HCV and more recently SARS-CoV-2. Circadian rhythms can affect the pharmacokinetics and efficacy of therapeutic agents and vaccines, providing fertile ground for the discovery of new antiviral therapies. An increased understanding of the role circadian systems play in virus replication and host immune responses has clinical implications for the management and treatment of viral diseases, highlighting the importance of virus-clock research.
Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model.
Wing PAC. et al, (2022), PLoS Pathog, 18
Are the Patterns of Cytomegalovirus Viral Load Seen After Solid Organ Transplantation Affected by Circadian Rhythm?
Rafferty H. et al, (2022), J Infect Dis, 226, 357 - 365
Time-of-Day Variation in SARS-CoV-2 RNA Levels during the Second Wave of COVID-19.
Zhuang X. et al, (2022), Viruses, 14
Reply to: 'Active HBV replication in hypoxic pericentral zone 3 is upregulated by multiple host factors including HIF-1α'.
Harris JM. et al, (2022), J Hepatol, 77, 267 - 268
Inflammatory Gene Expression Associates with Hepatitis B Virus cccDNA- but Not Integrant-Derived Transcripts in HBeAg Negative Disease.
Magri A. et al, (2022), Viruses, 14