Bim-mediated attrition of virus-specific CD8 T cells in chronic HBV infection

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Hepatitis B virus remains one of the top ten killers in the world today, causing around a million deaths every year from chronic liver disease, leading to liver failure and liver cancer. There is a vaccine to prevent spread, but this is of no use to the 400 million people estimated to already be chronically infected. There are now a number of drugs available to treat hepatitis B infection but these typically only suppress the virus rather than clear it; when the patient stops the treatment the virus level comes back up. The goal of the work proposed here is to allow us to develop a type of treatment supplement to boost immune control, such that costly and potentially toxic antiviral drugs would only need to be given for a short period. We will address this by parallel experiments using both a mouse model and also cells studied directly from patients, including those on the latest treatments available for hepatitis B virus infection. We have identified a critical defect in T cells (a key type of killer immune cell), which could account for their failure to control hepatitis B virus in patients with chronic infection. We have found that their T cells are triggered to commit suicide when they encounter hepatitis B virus; too few of these cells then survive to control the infection. This proposal aims to work out what drives this cell suicide and whether it can be safely blocked to allow a recovery of T cells. This could then switch the immune response back to the successful type seen in people who manage to control this infection naturally without requiring drug treatment.