Interferon- 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 both ZAP and ISG20 physically interact with HBV RNA; 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 retains antiviral activity against HBV replication by interacting with viral pregenomic (pg) RNA and subsequently interfering with pgRNA encapsidation. In addition, both ZAP and ISG20 are expressed at basal levels in hepatocytes, and can be further induced upon interferon stimulation, indicating their potential roles in host restriction of HBV. Here we propose to further elucidate the molecular mechanisms of ZAP/ISG20-mediated HBV RNA decay. The proposed Aims include: (1) The sequence element(s) of HBV RNA responsible for ZAP- and ISG20-mediated RNA degradation will be identified; (2) the physiologic role of ZAP and ISG20 in innate immunity-elicited anti-HBV responses will be determined; (3) co- factor(s) in ZAP- and ISG20-mediated HBV RNA decay will be identified through a proteomic approach, and the potential cooperative role between ZAP and ISG20 will also be investigated; (4) identification of the potential host RNA molecules targeted by ZAP and ISG20, including mRNA and miRNA. Elucidation of the molecular mechanisms of the intricate cellular antiviral response mediated by ZAP and ISG20 will shed light on cell biology and virus-host interaction during viral pathogenesis, and potentially lead to the development of novel therapeutics that exploit host molecules to control viral infection.

Public Health Relevance

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 related to the public health interest.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI103838-03
Application #
8850807
Study Section
Virology - B Study Section (VIRB)
Program Officer
Koshy, Rajen
Project Start
2014-06-01
Project End
2017-05-31
Budget Start
2015-06-01
Budget End
2017-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202