1003. Inhibition of HBV Replication In Vivo by HBx-Specific siRNA

Hepatitis B virus (HBV) causes acute and chronic hepatitis that could result in severe liver diseases such as cirrhosis and hepatocellular carcinoma. Because of the restricted host range of HBV, it has been difficult to study HBV replication in vivo and to test in vivo efficacy of possible antiviral therapeutics. In this study, we reproduced a naturally occurring HBV infection in mice by simply injecting HBV genome and also studied the effects of an HBV-specific short interfering RNA (siRNA) targeted to the X gene using this mouse model system. The viral replication cycle of HBV was resulted from the hydrodynamic transfection with the fragmented form of infectious HBV genome in immunocompetent mice. HBV envelope (HBe), HBV surface (HBs) antigens and viral DNA could be detected in the serum of the animals, followed by the induction of HBV-specific immune responses which mimics acute infection of HBV in humans. Also, the immunocompromized mice injected with the infectious HBV genome supported the prolonged replication of HBV mimicking the chronic infection of HBV in humans. In both systems, injection of siRNA targeted to the X gene region, where four major HBV transcript overlap, led to the dramatic inhibition of HBV replication up to 99% in the treated mice demonstrating the potential utility of HBx-specific siRNAs as anti-viral inhibitors for the treatment of chronic viral hepatitis. In summary, these mouse model systems offered opportunities to test in vivo efficacy of HBx-specific siRNAs for control of HBV replication.