Inhibition of Filovirus Replication by the Zinc Finger Antiviral Protein

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2006 Dec 22

PMID 17182693

Citations 137

Authors

Stefanie Muller

Peggy Moller

Matthew J Bick

Stephanie Wurr

Stephan Becker

Stephan Gunther

Beate M Kummerer

Affiliations

Soon will be listed here.

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.

Citing Articles

Infectious Subgenomic Amplicon Strategies for Japanese Encephalitis and West Nile Viruses.

Singh P, Le N, Karniychuk U J Med Virol. 2025; 97(2):e70205.

PMID: 39895481 PMC: 11788880. DOI: 10.1002/jmv.70205.

Mammalian ZAP and KHNYN independently restrict CpG-enriched avian viruses.

Becker J, Mickelson C, Pross L, Sanders A, Vogt E, Shepherd F bioRxiv. 2025; .

PMID: 39763980 PMC: 11703154. DOI: 10.1101/2024.12.23.629495.

Functional anatomy of zinc finger antiviral protein complexes.

Bohn J, Meagher J, Takata M, Goncalves-Carneiro D, Yeoh Z, Ohi M Nat Commun. 2024; 15(1):10834.

PMID: 39738020 PMC: 11685948. DOI: 10.1038/s41467-024-55192-z.

A minimal complex of KHNYN and zinc-finger antiviral protein binds and degrades single-stranded RNA.

Yeoh Z, Meagher J, Kang C, Bieniasz P, Smith J, Ohi M Proc Natl Acad Sci U S A. 2024; 121(52):e2415048121.

PMID: 39693345 PMC: 11670115. DOI: 10.1073/pnas.2415048121.

Endogenous ZAP is associated with altered Zika virus infection phenotype.

Le N, Singh P, Sabir A, Trus I, Karniychuk U Virol J. 2024; 21(1):285.

PMID: 39522048 PMC: 11549788. DOI: 10.1186/s12985-024-02557-x.

References

Gibb T, Norwood Jr D, Woollen N, Henchal E . Development and evaluation of a fluorogenic 5' nuclease assay to detect and differentiate between Ebola virus subtypes Zaire and Sudan. J Clin Microbiol. 2001; 39(11):4125-30. PMC: 88497. DOI: 10.1128/JCM.39.11.4125-4130.2001. View

Hoenen T, Groseth A, Kolesnikova L, Theriault S, Ebihara H, Hartlieb B . Infection of naive target cells with virus-like particles: implications for the function of ebola virus VP24. J Virol. 2006; 80(14):7260-4. PMC: 1489071. DOI: 10.1128/JVI.00051-06. View

Gibb T, Norwood Jr D, Woollen N, Henchal E . Development and evaluation of a fluorogenic 5'-nuclease assay to identify Marburg virus. Mol Cell Probes. 2001; 15(5):259-66. DOI: 10.1006/mcpr.2001.0369. View

Huang Y, Xu L, Sun Y, Nabel G . The assembly of Ebola virus nucleocapsid requires virion-associated proteins 35 and 24 and posttranslational modification of nucleoprotein. Mol Cell. 2002; 10(2):307-16. DOI: 10.1016/s1097-2765(02)00588-9. View

Gao G, Guo X, Goff S . Inhibition of retroviral RNA production by ZAP, a CCCH-type zinc finger protein. Science. 2002; 297(5587):1703-6. DOI: 10.1126/science.1074276. View

Bredenbeek P, Kooi E, Lindenbach B, Huijkman N, Rice C, Spaan W . A stable full-length yellow fever virus cDNA clone and the role of conserved RNA elements in flavivirus replication. J Gen Virol. 2003; 84(Pt 5):1261-1268. DOI: 10.1099/vir.0.18860-0. View

Bick M, Carroll J, Gao G, Goff S, Rice C, MacDonald M . Expression of the zinc-finger antiviral protein inhibits alphavirus replication. J Virol. 2003; 77(21):11555-62. PMC: 229374. DOI: 10.1128/jvi.77.21.11555-11562.2003. View

Kolesnikova L, Bamberg S, Berghofer B, Becker S . The matrix protein of Marburg virus is transported to the plasma membrane along cellular membranes: exploiting the retrograde late endosomal pathway. J Virol. 2004; 78(5):2382-93. PMC: 369247. DOI: 10.1128/jvi.78.5.2382-2393.2004. View

Asper M, Sternsdorf T, Hass M, Drosten C, Rhode A, Schmitz H . Inhibition of different Lassa virus strains by alpha and gamma interferons and comparison with a less pathogenic arenavirus. J Virol. 2004; 78(6):3162-9. PMC: 353741. DOI: 10.1128/jvi.78.6.3162-3169.2004. View

10.

Dolnik O, Volchkova V, Garten W, Carbonnelle C, Becker S, Kahnt J . Ectodomain shedding of the glycoprotein GP of Ebola virus. EMBO J. 2004; 23(10):2175-84. PMC: 424403. DOI: 10.1038/sj.emboj.7600219. View

11.

Hartman A, Towner J, Nichol S . A C-terminal basic amino acid motif of Zaire ebolavirus VP35 is essential for type I interferon antagonism and displays high identity with the RNA-binding domain of another interferon antagonist, the NS1 protein of influenza A virus. Virology. 2004; 328(2):177-84. DOI: 10.1016/j.virol.2004.07.006. View

12.

BOWEN E, Lloyd G, Harris W, Platt G, Baskerville A, Vella E . Viral haemorrhagic fever in southern Sudan and northern Zaire. Preliminary studies on the aetiological agent. Lancet. 1977; 1(8011):571-3. DOI: 10.1016/s0140-6736(77)92001-3. View

13.

Rice C, Levis R, Strauss J, Huang H . Production of infectious RNA transcripts from Sindbis virus cDNA clones: mapping of lethal mutations, rescue of a temperature-sensitive marker, and in vitro mutagenesis to generate defined mutants. J Virol. 1987; 61(12):3809-19. PMC: 255997. DOI: 10.1128/JVI.61.12.3809-3819.1987. View

14.

Muhlberger E, Weik M, Volchkov V, Klenk H, Becker S . Comparison of the transcription and replication strategies of marburg virus and Ebola virus by using artificial replication systems. J Virol. 1999; 73(3):2333-42. PMC: 104478. DOI: 10.1128/JVI.73.3.2333-2342.1999. View

15.

Guo X, Carroll J, MacDonald M, Goff S, Gao G . The zinc finger antiviral protein directly binds to specific viral mRNAs through the CCCH zinc finger motifs. J Virol. 2004; 78(23):12781-7. PMC: 525010. DOI: 10.1128/JVI.78.23.12781-12787.2004. View

16.

Hass M, Golnitz U, Muller S, Becker-Ziaja B, Gunther S . Replicon system for Lassa virus. J Virol. 2004; 78(24):13793-803. PMC: 533938. DOI: 10.1128/JVI.78.24.13793-13803.2004. View

17.

Hoenen T, Volchkov V, Kolesnikova L, Mittler E, Timmins J, Ottmann M . VP40 octamers are essential for Ebola virus replication. J Virol. 2005; 79(3):1898-905. PMC: 544139. DOI: 10.1128/JVI.79.3.1898-1905.2005. View

18.

Boehmann Y, Enterlein S, Randolf A, Muhlberger E . A reconstituted replication and transcription system for Ebola virus Reston and comparison with Ebola virus Zaire. Virology. 2005; 332(1):406-17. DOI: 10.1016/j.virol.2004.11.018. View

19.

Kash J, Muhlberger E, Carter V, Grosch M, Perwitasari O, Proll S . Global suppression of the host antiviral response by Ebola- and Marburgviruses: increased antagonism of the type I interferon response is associated with enhanced virulence. J Virol. 2006; 80(6):3009-20. PMC: 1395418. DOI: 10.1128/JVI.80.6.3009-3020.2006. View

20.

Reid S, Leung L, Hartman A, Martinez O, Shaw M, Carbonnelle C . Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation. J Virol. 2006; 80(11):5156-67. PMC: 1472181. DOI: 10.1128/JVI.02349-05. View