Discovering the mechanisms underlying HBV persistence in chronic liver disease

Chronic hepatitis B is one of the world?s unconquered diseases and presents as a spectrum of liver disease, reflecting a dynamic interaction between the virus and immune system. Although current treatments suppress hepatitis B virus (HBV), they are not curative and patients are at risk of developing progressive liver disease. The persistence of the HBV DNA genome and inadequate host immune responses limit progress towards a cure. HBV replication varies spatially within the liver and temporally between disease phases, suggesting localised hepatocyte-intrinsic and liver-resident immune resistance mechanisms. We have shown that oxygen levels influence HBV replication, leading to the hypothesis that hypoxia is a central unifying pathway regulating hepatocyte susceptibility to HBV infection and local immune control. We have developed single-molecule sensitive methods to visualise HBV RNA molecules, offering unprecedented sensitivity to quantify viral transcription in situ and new insights into the behaviour of individual cells that are masked in population-based studies. Combining this with spatial transcriptomics provides an integrated approach to study both viral and immune parameters in the liver and a step-change in our understanding of this chronic disease and paving the way for new therapies.