Favipiravir can evoke lethal mutagenesis and extinction of foot-and-mouth disease virus.
Antiviral agents are increasingly considered an option for veterinary medicine. An understanding of their mechanism of activity is important to plan their administration either as monotherapy or in combination with other agents. Previous studies have shown that the broad spectrum antiviral agent favipiravir (T-705) and its derivatives T-1105 and T-1106 are efficient inhibitors of foot-and-mouth disease virus (FMDV) replication in cell culture and in vivo. However, no mechanism for their activity against FMDV has been proposed. In the present study we show that favipiravir (T-705) can act as a lethal mutagen for FMDV in cell culture. Evidence includes virus extinction associated with increase in mutation frequency in the mutant spectrum of 860 residues of the 3D (polymerase)-coding region, and a decrease of specific infectivity while the consensus nucleotide sequence of the region analyzed remained invariant. The mutational spectrum evoked by favipiravir differs from that observed with other viruses in that no predominant transition type is observed, indicating that a movement towards A,U- or G,C-rich regions of sequence space is not a prerequisite for virus extinction. We discuss prospects for the use of favipiravir to assist in the control of FMDV, and its possible broader use in veterinary medicine as an extension of its current status as antiviral agent for human influenza virus.
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, E-28049, Madrid, Spain.
Ana Isabel
AI
de Avila
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, E-28049, Madrid, Spain.
Elena
E
Moreno
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, E-28049, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Universitat Autònoma de Barcelona, 08035, Barcelona, Spain. Electronic address: cperales@cbm.csic.es.
Celia
C
Perales
Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, E-28049, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain. Electronic address: edomingo@cbm.csic.es.
Esteban
E
Domingo
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003412:Cricetulus; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D029544:Foot-and-Mouth Disease Virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D020128:Inhibitory Concentration 50; D016296:Mutagenesis; D009153:Mutagens / Q000494:pharmacology*; D059645:Mutation Rate; D011719:Pyrazines / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
D000577:Amides; D000998:Antiviral Agents; D009153:Mutagens; D011719:Pyrazines; C462182:favipiravir
Antiviral agent; Error threshold; Mutational spectrum; Quasispecies