EUCLIDEAN · Acquired adaptive immune cell dysfunction and restoration in chronic hepatitis B

This proposal aims to investigate the development of dysfunctional adaptive immune cells during chronic hepatitis B virus (HBV) infection and to develop new strategies to reprogram them into functional cells with potent antiviral activity. Our hypothesis, based on extensive preliminary data, is that HBV induces a unique type of adaptive immune cell dysfunction that differs from that observed in other viral infections or cancer. To investigate this, we will use unique mouse models of HBV pathogenesis, several of which have been generated ad hoc for this proposal, and well-characterized patient cohorts to identify, dissect and target dysregulated pathways that cause adaptive immune cell dysfunction during chronic hepatitis B. State-of-the-art static and dynamic imaging will be employed to analyze the behavior of adaptive immune cells that ultimately differentiate into dysfunctional cells in the liver at unprecedented levels of spatial and temporal resolution. In parallel, high-dimensional flow cytometry and single cell sequencing in mouse models of HBV pathogenesis and in chronically infected patients will reveal the underlying proteogenomic landscape and heterogeneity that cause adaptive immune cell dysfunction. Finally, immunoregulatory mechanisms already identified in preliminary work or that will emerge from the above analyses will be targeted both in vitro and in vivo. By studying all the main players of HBV immunity together with state-of-the-art techniques and by interconnecting research with mouse models with analyses of human samples, we are in a unique position to make fundamental leaps in our understanding of adaptive immunity and viral pathogenesis. We are confident that the results emerging from this proposal will have the potential to guide the design of novel, rational strategies to direct the immune system to terminate chronic HBV infection and its associated costs and complications.