A role for low oxygen and hypoxia inducible factors to regulate viral replication and 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 liver disease which can progress to hepatocellular carcinoma (HCC): a metastatic cancer with limited therapeutic options. We recently discovered that low oxygen environments, naturally found in the liver, enhance HBV and HCV replication and this is mediated by hypoxia inducible transcription factors (HIFs) regulating host pathways that are essential for viral replication.

HIFs direct 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. Current HCC therapies show limited efficacy and recent research efforts have focused on the molecular profiling of tumours to identify gene signatures that predict disease outcome and response to therapy. 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 HIF in viral-associated HCC heterogeneity and inform stratified approaches for new treatments.