||Studies on Innate Immune Activation by HBV Infection and Its Sensing Mechanism in Hepatocytes
Pattern recognition receptors (PRRs) recognize invading viruses mainly by sensing viral nucleic acid and trigger key antiviral immune responses in the innate immune system that act as a front line of host defense against viral infection. Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause both acute and chronic liver disease, and more than 240 million people worldwide are chronic HBV carriers that have a high risk for liver cirrhosis or hepatocellular carcinoma. Current approved therapies of chronic hepatitis B include administration of antivirally active interferon-α (IFN-α) and inhibitors of viral reverse transcription have severe side effects and a risk to develop of drug resistant mutations. The nucleic acid sensor(s) for HBV and the host innate immune response against HBV infection has not been identified. Thus, understanding of the nature of innate immunity induced by HBV will aid to characterize the immunopathogenesis of HBV infection and to further develop novel innate immune-based antiviral approaches for HBV infection or optimize the current therapy regimens of HBV. Therefore, this study tried to elucidate the innate immune activation upon HBV infection and clarify the mechanism of this activation.The results of this study demonstrated that type III but not type I IFNs are predominantly induced in human hepatocytes in response to HBV infection, through retinoic acid-inducible gene-I (RIG-I)-mediated sensing of the 5’-ε region of HBV pregenomic RNA (pgRNA), and the induced type III IFN exhibits potent physiologicalantiviral activities. In addition, RIG-I could also directly suppress HBV replication in an IFN signaling-independent manner that counteracts the interaction of HBV polymerase (P protein) with the 5’-ε region, which is essential for initiation of viral pgRNA encapsidation during HBV replication. Furthermore, liposome-mediated delivery and vector-based expression of this ε region-derived RNA (εRNA) in liver abolished the HBV replication in human hepatocyte-chimeric mice.The observations of this study reveal an innate recognition mechanism by which RIG-I dually functions as an HBV sensor activating innate signaling and to counteract viral polymerase in human hepatocytes. Moreover, this study also evaluate the therapeutic potential of the εRNA for the control of HBV infection, which may provide a better approach to the strategies for development of nucleic acid medicine, and offer an attractive clinical option for the therapy against not only HBV but also possibly other II virus infections.
Hokkaido University（北海道大学）. 博士(理学)