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Article: T-705 (favipiravir) induces lethal mutagenesis in influenza a H1N1 viruses in vitro
Title | T-705 (favipiravir) induces lethal mutagenesis in influenza a H1N1 viruses in vitro |
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Authors | |
Issue Date | 2013 |
Citation | Journal of Virology, 2013, v. 87, n. 7, p. 3741-3751 How to Cite? |
Abstract | Several 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 Identifier | http://hdl.handle.net/10722/311937 |
ISSN | 2021 Impact Factor: 6.549 2020 SCImago Journal Rankings: 2.617 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Baranovich, Tatiana | - |
dc.contributor.author | Wong, Sook San | - |
dc.contributor.author | Armstrong, Jianling | - |
dc.contributor.author | Marjuki, Henju | - |
dc.contributor.author | Webby, Richard J. | - |
dc.contributor.author | Webster, Robert G. | - |
dc.contributor.author | Govorkova, Elena A. | - |
dc.date.accessioned | 2022-04-06T04:31:48Z | - |
dc.date.available | 2022-04-06T04:31:48Z | - |
dc.date.issued | 2013 | - |
dc.identifier.citation | Journal of Virology, 2013, v. 87, n. 7, p. 3741-3751 | - |
dc.identifier.issn | 0022-538X | - |
dc.identifier.uri | http://hdl.handle.net/10722/311937 | - |
dc.description.abstract | Several 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.language | eng | - |
dc.relation.ispartof | Journal of Virology | - |
dc.title | T-705 (favipiravir) induces lethal mutagenesis in influenza a H1N1 viruses in vitro | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1128/JVI.02346-12 | - |
dc.identifier.scopus | eid_2-s2.0-84875107202 | - |
dc.identifier.volume | 87 | - |
dc.identifier.issue | 7 | - |
dc.identifier.spage | 3741 | - |
dc.identifier.epage | 3751 | - |
dc.identifier.eissn | 1098-5514 | - |
dc.identifier.isi | WOS:000315957100012 | - |
dc.identifier.f1000 | 717971369 | - |