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Article: Neuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo

TitleNeuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivo
Authors
Issue Date2007
PublisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/
Citation
Journal Of Virology, 2007, v. 81 n. 22, p. 12418-12426 How to Cite?
AbstractEffective antiviral drugs are essential for early control of an influenza pandemic. It is therefore crucial to evaluate the possible threat posed by neuraminidase (NA) inhibitor-resistant influenza viruses with pandemic potential. Four NA mutations (E119G, H274Y, R292K, and N294S) that have been reported to confer resistance to NA inhibitors were each introduced into recombinant A/Vietnam/1203/04 (VN1203) H5N1 influenza virus. For comparison, the same mutations were introduced into recombinant A/Puerto Rico/8/34 (PR8) H1N1 influenza virus. The E119G and R292K mutations significantly compromised viral growth in vitro, but the H274Y and N294S mutations were stably maintained in VN1203 and PR8 viruses. In both backgrounds, the H274Y and N294S mutations conferred resistance to oseltamivir carboxylate (50% inhibitory concentration [IC50] increases, >250-fold and >20-fold, respectively), and the N294S mutation reduced susceptibility to zanamivir (IC50 increase, >3.0-fold). Although the H274Y and N294S mutations did not compromise the replication efficiency of VN1203 or PR8 viruses in vitro, these mutations slightly reduced the lethality of PR8 virus in mice. However, the VN1203 virus carrying either the H274Y or N294S mutation exhibited lethality similar to that of the wild-type VN1203 virus. The different enzyme kinetic parameters (Vmax and Km) of avian-like VN1203 NA and human-like PR8 NA suggest that resistance-associated NA mutations can cause different levels of functional loss in NA glycoproteins of the same subtype. Our results suggest that NA inhibitor-resistant H5N1 variants may retain the high pathogenicity of the wild-type virus in mammalian species. Patients receiving NA inhibitors for H5N1 influenza virus infection should be closely monitored for the emergence of resistant variants. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Persistent Identifierhttp://hdl.handle.net/10722/179805
ISSN
2015 Impact Factor: 4.606
2015 SCImago Journal Rankings: 3.347
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorYen, HLen_US
dc.contributor.authorIlyushina, NAen_US
dc.contributor.authorSalomon, Ren_US
dc.contributor.authorHoffmann, Een_US
dc.contributor.authorWebster, RGen_US
dc.contributor.authorGovorkova, EAen_US
dc.date.accessioned2012-12-19T10:04:58Z-
dc.date.available2012-12-19T10:04:58Z-
dc.date.issued2007en_US
dc.identifier.citationJournal Of Virology, 2007, v. 81 n. 22, p. 12418-12426en_US
dc.identifier.issn0022-538Xen_US
dc.identifier.urihttp://hdl.handle.net/10722/179805-
dc.description.abstractEffective antiviral drugs are essential for early control of an influenza pandemic. It is therefore crucial to evaluate the possible threat posed by neuraminidase (NA) inhibitor-resistant influenza viruses with pandemic potential. Four NA mutations (E119G, H274Y, R292K, and N294S) that have been reported to confer resistance to NA inhibitors were each introduced into recombinant A/Vietnam/1203/04 (VN1203) H5N1 influenza virus. For comparison, the same mutations were introduced into recombinant A/Puerto Rico/8/34 (PR8) H1N1 influenza virus. The E119G and R292K mutations significantly compromised viral growth in vitro, but the H274Y and N294S mutations were stably maintained in VN1203 and PR8 viruses. In both backgrounds, the H274Y and N294S mutations conferred resistance to oseltamivir carboxylate (50% inhibitory concentration [IC50] increases, >250-fold and >20-fold, respectively), and the N294S mutation reduced susceptibility to zanamivir (IC50 increase, >3.0-fold). Although the H274Y and N294S mutations did not compromise the replication efficiency of VN1203 or PR8 viruses in vitro, these mutations slightly reduced the lethality of PR8 virus in mice. However, the VN1203 virus carrying either the H274Y or N294S mutation exhibited lethality similar to that of the wild-type VN1203 virus. The different enzyme kinetic parameters (Vmax and Km) of avian-like VN1203 NA and human-like PR8 NA suggest that resistance-associated NA mutations can cause different levels of functional loss in NA glycoproteins of the same subtype. Our results suggest that NA inhibitor-resistant H5N1 variants may retain the high pathogenicity of the wild-type virus in mammalian species. Patients receiving NA inhibitors for H5N1 influenza virus infection should be closely monitored for the emergence of resistant variants. Copyright © 2007, American Society for Microbiology. All Rights Reserved.en_US
dc.languageengen_US
dc.publisherAmerican Society for Microbiology. The Journal's web site is located at http://jvi.asm.org/en_US
dc.relation.ispartofJournal of Virologyen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntiviral Agents - Pharmacologyen_US
dc.subject.meshDrug Resistance, Viral - Geneticsen_US
dc.subject.meshEnzyme Inhibitors - Pharmacologyen_US
dc.subject.meshHumansen_US
dc.subject.meshInfluenza A Virus, H5n1 Subtype - Enzymology - Genetics - Pathogenicityen_US
dc.subject.meshInfluenza, Human - Virologyen_US
dc.subject.meshKineticsen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred Balb Cen_US
dc.subject.meshNeuraminidase - Antagonists & Inhibitors - Chemistry - Geneticsen_US
dc.subject.meshOseltamivir - Pharmacologyen_US
dc.subject.meshViral Proteins - Antagonists & Inhibitors - Chemistry - Geneticsen_US
dc.subject.meshVirulence - Geneticsen_US
dc.subject.meshVirus Replication - Geneticsen_US
dc.titleNeuraminidase inhibitor-resistant recombinant A/Vietnam/1203/04 (H5N1) influenza viruses retain their replication efficiency and pathogenicity in vitro and in vivoen_US
dc.typeArticleen_US
dc.identifier.emailYen, HL: hyen@hku.hken_US
dc.identifier.authorityYen, HL=rp00304en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1128/JVI.01067-07en_US
dc.identifier.pmid17855542-
dc.identifier.scopuseid_2-s2.0-36048996081en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-36048996081&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume81en_US
dc.identifier.issue22en_US
dc.identifier.spage12418en_US
dc.identifier.epage12426en_US
dc.identifier.eissn1098-5514-
dc.identifier.isiWOS:000254065400032-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridYen, HL=7102476668en_US
dc.identifier.scopusauthoridIlyushina, NA=6506741015en_US
dc.identifier.scopusauthoridSalomon, R=12786463900en_US
dc.identifier.scopusauthoridHoffmann, E=7201369718en_US
dc.identifier.scopusauthoridWebster, RG=36048363100en_US
dc.identifier.scopusauthoridGovorkova, EA=7003837718en_US

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