title: Inhibition of hepatitis B virus replication by the host zinc finger antiviral protein.
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-α 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.
authors.affiliation: Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America.
authors.forename: Richeng
authors.initials: R
authors.lastname: Mao
authors.forename: Hui
authors.initials: H
authors.lastname: Nie
authors.forename: Dawei
authors.initials: D
authors.lastname: Cai
authors.forename: Jiming
authors.initials: J
authors.lastname: Zhang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Liu
authors.forename: Ran
authors.initials: R
authors.lastname: Yan
authors.forename: Andrea
authors.initials: A
authors.lastname: Cuconati
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Block
authors.forename: Ju-Tao
authors.initials: JT
authors.lastname: Guo
authors.forename: Haitao
authors.initials: H
authors.lastname: Guo
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000276:immunology / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000378:metabolism / Q000821:virology; D022781:Hepatocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D012367:RNA, Viral / Q000096:biosynthesis / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D004279:DNA, Viral; D010446:Peptide Fragments; D020033:Protein Isoforms; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C527496:ZC3HAV1 protein, human; C465959:Zc3hav1 protein, rat