title: Inhibition of filovirus replication by the zinc finger antiviral protein.
abstract: The zinc finger antiviral protein (ZAP) was recently shown to inhibit Moloney murine leukemia virus and Sindbis virus replication. We tested whether ZAP also acts against Ebola virus (EBOV) and Marburg virus (MARV). Antiviral effects were observed after infection of cells expressing the N-terminal part of ZAP fused to the product of the zeocin resistance gene (NZAP-Zeo) as well as after infection of cells inducibly expressing full-length ZAP. EBOV was inhibited by up to 4 log units, whereas MARV was inhibited between 1 to 2 log units. The activity of ZAP was dependent on the integrity of the second and fourth zinc finger motif, as tested with cell lines expressing NZAP-Zeo mutants. Heterologous expression of EBOV- and MARV-specific sequences fused to a reporter gene suggest that ZAP specifically targets L gene sequences. The activity of NZAP-Zeo in this assay was also dependent on the integrity of the second and fourth zinc finger motif. Time-course experiments with infectious EBOV showed that ZAP reduces the level of L mRNA before the level of genomic or antigenomic RNA is affected. Transient expression of ZAP decreased the activity of an EBOV replicon system by up to 95%. This inhibitory effect could be partially compensated for by overexpression of L protein. In conclusion, the data demonstrate that ZAP exhibits antiviral activity against filoviruses, presumably by decreasing the level of viral mRNA.
authors.affiliation: Department of Virology, Bernhard-Nocht-Strasse 74, Bernhard-Nocht-Institute for Tropical Medicine, 20359 Hamburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Müller
authors.forename: Peggy
authors.initials: P
authors.lastname: Möller
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bick
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wurr
authors.forename: Stephan
authors.initials: S
authors.lastname: Becker
authors.forename: Stephan
authors.initials: S
authors.lastname: Günther
authors.forename: Beate M
authors.initials: BM
authors.lastname: Kümmerer
mesh_terms: D000818:Animals; D001483:Base Sequence; D001761:Bleomycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics; D029043:Ebolavirus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D016563:Filoviridae / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D005814:Genes, Viral; D029024:Marburgvirus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D051381:Rats; D012093:Replicon; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D004279:DNA, Viral; D012333:RNA, Messenger; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D014764:Viral Proteins; C465959:Zc3hav1 protein, rat; D001761:Bleomycin; C105427:Zeocin