Interferon-a is an approved medication for chronic hepatitis B. In the screening of interferon stimulated genes (ISG) for their potential antiviral activity against HBV replication, we identified two host proteins, specifically zinc finger antivirl protein (ZAP) and ISG20, which inhibit HBV replication primarily through posttranscriptional downregulation of viral RNA. Our data also demonstrated that while the integrity of the four CCCH-type zinc finger motifs is required for ZAP mediated HBV RNA degradation, the reduction of HBV RNA by ISG20 depends on its ribonuclease activity. Interestingly, the enzymatically inactive form of ISG20 still retains antiviral activity against HBV replication by interfering vira pregenomic RNA encapsidation into nucleocapsid. In addition, both ZAP and ISG20 have basal level expressions in hepatocytes, and can be further induced upon interferon stimulation, indicating their potential roles in host restriction of HBV. In this application we will further elucidate the molecular mechanisms of ZAP/ISG20 mediated HBV RNA decay, the proposed Aims include: (1) The potential physical interaction between HBV RNA and ZAP/ISG20 will be determined; (2) The sequence element(s) within HBV RNA responsible for ZAP and ISG20 mediated RNA degradation will be identified; (3) The physiologic role of ZAP and ISG20 in IFN elicited anti-HBV response will be determined; (4) Co-factor(s) in ZAP and ISG20 mediated HBV RNA decay will be identified through proteome approach, and the potential cooperative role between ZAP and ISG20 will also be studied. Understanding the molecular mechanisms of such intricate cellular antiviral response mediated by ZAP and ISG20 will advance the understanding of how pathogen and host cell interact during viral pathogenesis, and potentially open a new venue for development of novel therapeutics that exploit such host intracellular molecules to control chronic HBV infection.
Hepatitis B virus infection is a severe public health problem affecting about 350 million individuals worldwide and at least 1.2 million individuals in the Unite States. Chronic hepatitis B patients have a high risk of occurrence of hepatocirrhosis and liver cancer. The proposed study on the antiviral mechanism of host protein ZAP/ISG20 against HBV would lead to the better understanding of the virus host interaction and development of novel therapeutics for treatment of hepatitis B. Therefore; our research is highly relavant to the publichealth interest.
