Professor of Molecular Virology
Our research focuses on understanding early infection events that define cellular and tissue tropism of clinically important viruses. Preventing viral induced disease begins with an understanding of the host factors that define susceptibility to infection.
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. We recently discovered that the low oxygen environment naturally found in the liver enhances HBV and HCV replication and this is mediated by hypoxia inducible transcription factors (HIFs). Inhibiting HIFs or suppressing their expression limits virus infection, highlighting new therapeutic approaches.
Different anatomical sites experience varying oxygen tensions and we hypothesize that local changes in oxygen tension define active or latent states of viral replication. Immune cells encounter variable oxygen tensions as they migrate from the periphery into tissue and are a major target for HIV infection. Studies in our laboratory show that hypoxia limits HIV transcription and HIF-stabilizing drugs potentiate viral reactivation from latent sites of infection. Understanding the role of hypoxia induced signalling and metabolic effects on HIV transcription and latency will inform the development of new ‘curative strategies’.
HIFs coordinate extensive transcriptional responses that enable a cell to respond to diverse physiological or pathophysiological signals. Hepatitis B and C viruses activate HIFs and promote a ‘pseudohypoxic’ state that potentiates viral replication. Understanding how viruses influence host gene transcription is fundamental and profiling HIF-transcriptional targets in infected cells provides a unique opportunity to define the role of HIFs in viral-associated pathologies.
The circadian clock components BMAL1 and REV-ERBα regulate flavivirus replication
Zhuang X. et al, (2019), Nature Communications, 10
Bacterial flagellin promotes viral entry via an NF-kB and Toll Like Receptor 5 dependent pathway.
Benedikz EK. et al, (2019), Sci Rep, 9
A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis.
Wing PA. et al, (2019), Life Sci Alliance, 2
Hepatitis C virus infection is associated with hepatic and adipose tissue insulin resistance that improves after viral cure.
Lim TR. et al, (2019), Clin Endocrinol (Oxf), 90, 440 - 448
Insights From Deep Sequencing of the HBV Genome—Unique, Tiny, and Misunderstood
McNaughton AL. et al, (2019), Gastroenterology, 156, 384 - 399