Immunopathogenesis of hepatitis D virus infection

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Infection with the hepatitis D virus (HDV) induces the least frequent but most severe form of viral hepatitis. This process is thought to be immune-mediated, however there is not sufficient data available to support this hypothesis. Chronic hepatitis D results from either simultaneous infection with the hepatitis B virus (HBV) or from superinfection of patients that are already infected with HBV, as the HBV surface protein is needed to package the HDV genome. The currently available treatment options are limited to pegylated interferon alpha with a response rate of 25% and Bulevirtide, where long-term data are still expected. The long-term goal of this project is to advance the understanding of the immunopathogenesis of HDV infection. The overall objective of this proposal is to define the role of CD8+ T cells in viral control and liver disease pathogenesis. The central hypothesis is, that CD8+ T cells are important for the control of HDV, but that they are also involved in the induction of liver disease pathogenesis during chronic HDV infection. This will be tested by pursuing two specific aims: 1). Identify the immunological mechanism of HDV control. The working hypothesis is that strong and polyfunctional HDV-specific CD8+ T cells are contributing to HDV clearance. 2). Identify the immunological mechanism of liver disease pathogenesis. The working hypothesis is that bulk CD8+ T cells contribute to liver disease pathogenesis in chronic HDV infection through activation by inflammatory cytokines. The research proposed is significant, because it will elicit the role of CD8+ T cells in the immunopathogenesis of HDV infection and provide scientific justification whether they shall be targeted by personalized immunomodulatory treatment options.