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Journal article
Inhibition of Hepatitis B Virus Replication by the Host Zinc Finger Antiviral Protein
PLoS pathogens, v 9(7), pp e1003494-e1003494
01 Jul 2013
PMID: 23853601
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The zinc finger antiviral protein (ZAP) is a mammalian host restriction factor that inhibits the replication of a variety of RNA viruses, including retroviruses, alphaviruses and filoviruses, through interaction with the ZAP-responsive elements (ZRE) in viral RNA, and recruiting the exosome to degrade RNA substrate. Hepatitis B virus (HBV) is a pararetrovirus that replicates its genomic DNA via reverse transcription of a viral pregenomic (pg) RNA precursor. Here, we demonstrate that the two isoforms of human ZAP (hZAP-L and -S) inhibit HBV replication in human hepatocyte-derived cells through posttranscriptional down-regulation of viral pgRNA. Mechanistically, the zinc finger motif-containing N-terminus of hZAP is responsible for the reduction of HBV RNA, and the integrity of the four zinc finger motifs is essential for ZAP to bind to HBV RNA and fulfill its antiviral function. The ZRE sequences conferring the susceptibility of viral RNA to ZAP-mediated RNA decay were mapped to the terminal redundant region (nt 1820-1918) of HBV pgRNA. In agreement with its role as a host restriction factor and as an innate immune mediator for HBV infection, ZAP was upregulated in cultured primary human hepatocytes and hepatocyte-derived cells upon IFN-alpha treatment or IPS-1 activation, and in the livers of hepatitis B patients during immune active phase. Knock down of ZAP expression increased the level of HBV RNA and partially attenuated the antiviral effect elicited by IPS-1 in cell cultures. In summary, we demonstrated that ZAP is an intrinsic host antiviral factor with activity against HBV through down-regulation of viral RNA, and that ZAP plays a role in the innate control of HBV replication. Our findings thus shed light on virus-host interaction, viral pathogenesis, and antiviral approaches.
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Details
- Title
- Inhibition of Hepatitis B Virus Replication by the Host Zinc Finger Antiviral Protein
- Creators
- Richeng Mao - Drexel UniversityHui Nie - Drexel UniversityDawei Cai - Drexel UniversityJiming Zhang - Huashan HospitalHongyan Liu - Huashan HospitalRan Yan - Drexel UniversityAndrea Cuconati - Hepatitis B FoundationTimothy M. Block - Drexel UniversityJu-Tao Guo - Drexel UniversityHaitao Guo - Drexel University
- Publication Details
- PLoS pathogens, v 9(7), pp e1003494-e1003494
- Publisher
- Public Library Science
- Number of pages
- 18
- Grant note
- 2012ZX10002007-001-002; 2013ZX10002001 / Major Science and Technology Special Project 81071354; 81201277 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC) Hepatitis B Foundation Hepatitis B Foundation through Commonwealth of Pennsylvania R21AI088424 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) R21AI088424; R01AI094474 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 20120071120099 / Doctoral Fund of Ministry of Education of China; Ministry of Education, China Chinese Scholarship Council; China Scholarship Council
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000322316700037
- Scopus ID
- 2-s2.0-84884747041
- Other Identifier
- 991019168485104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Parasitology
- Virology