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Article: T-705 (favipiravir) induces lethal mutagenesis in influenza a H1N1 viruses in vitro

TitleT-705 (favipiravir) induces lethal mutagenesis in influenza a H1N1 viruses in vitro
Authors
Issue Date2013
Citation
Journal of Virology, 2013, v. 87, n. 7, p. 3741-3751 How to Cite?
AbstractSeveral novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P<0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families. © 2013, American Society for Microbiology.
Persistent Identifierhttp://hdl.handle.net/10722/311937
ISSN
2021 Impact Factor: 6.549
2020 SCImago Journal Rankings: 2.617
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorBaranovich, Tatiana-
dc.contributor.authorWong, Sook San-
dc.contributor.authorArmstrong, Jianling-
dc.contributor.authorMarjuki, Henju-
dc.contributor.authorWebby, Richard J.-
dc.contributor.authorWebster, Robert G.-
dc.contributor.authorGovorkova, Elena A.-
dc.date.accessioned2022-04-06T04:31:48Z-
dc.date.available2022-04-06T04:31:48Z-
dc.date.issued2013-
dc.identifier.citationJournal of Virology, 2013, v. 87, n. 7, p. 3741-3751-
dc.identifier.issn0022-538X-
dc.identifier.urihttp://hdl.handle.net/10722/311937-
dc.description.abstractSeveral novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P<0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families. © 2013, American Society for Microbiology.-
dc.languageeng-
dc.relation.ispartofJournal of Virology-
dc.titleT-705 (favipiravir) induces lethal mutagenesis in influenza a H1N1 viruses in vitro-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1128/JVI.02346-12-
dc.identifier.scopuseid_2-s2.0-84875107202-
dc.identifier.volume87-
dc.identifier.issue7-
dc.identifier.spage3741-
dc.identifier.epage3751-
dc.identifier.eissn1098-5514-
dc.identifier.isiWOS:000315957100012-
dc.identifier.f1000717971369-

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