Our research group has identified a cytosolic RNA sensor RIG-I (retinoic acid-inducible gene-I) as an innate sensor for hepatitis B virus (HBV) infection in human hepatocytes.

HBV is a hepatotropic DNA virus and causes hepatic inflammation associated with substantial morbidity worldwide. HBV is a major causative factor associated with not only inflammation but also cirrhosis and even cancer of the liver. However, it was not fully clarified about how HBV is sensed by host innate immune system, which is the first step of host defense against microbial infection. In this study, we have revealed that HBV infection is sensed by the RIG-I protein through its recognition of certain viral RNA (pregenomic RNA) within the cells, which triggers a predominant production of type III interferons, a well-known antiviral protein. We further determined that a key element for the RIG-I-mediated recognition is the 5′-ε region of HBV pregenomic RNA, which was previously reported to take a stem-loop structure and serve as a binding site of HBV polymerase, an essential enzyme for viral propagation. In relation to this, we also discovered a novel role of RIG-I as a direct antiviral factor that can competitively inhibit the interaction of HBV polymerase with the 5′-ε region of viral genome.

Finally, based on these results, we found that expression of this ε region-derived RNA could suppress HBV propagation in human hepatocyte-chimeric mice. These findings indicated that RIG-I dually functions not only as an HBV sensor but also as a counteractor against viral polymerase in human hepatocyte, and also suggest that the ε region-derived RNA would be a therapeutic tool for the treatment of HBV infection.

Akinori Takaoka, Professor, Division of Signaling in Cancer and Immunology; Director, Institute for Genetic Medicine, Hokkaido University

TEL: +81-11-706-5020 / 5536

E-mail: takaoka@igm.hokudai.ac.jp