title: Molecular dissection of a viral quasispecies under mutagenic treatment: positive correlation between fitness loss and mutational load.
abstract: Low fidelity replication and the absence of error-repair activities in RNA viruses result in complex and adaptable ensembles of related genomes in the viral population, termed quasispecies, with important implications for natural infections. Theoretical predictions suggested that elevated replication error rates in RNA viruses might be near to a maximum compatible with viral viability. This fact encouraged the use of mutagenic nucleosides as a new antiviral strategy to induce viral extinction through increased replication error rates. Despite extensive evidence of lethal mutagenesis of RNA viruses by different mutagenic compounds, a detailed picture of the infectivity of individual genomes and its relationship with the mutations accumulated is lacking. Here, we report a molecular analysis of a foot-and-mouth disease virus population previously subjected to heavy mutagenesis to determine whether a correlation between increased mutagenesis and decreased fitness existed. Plaque-purified viruses isolated from a ribavirin-treated quasispecies presented decreases of up to 200-fold in infectivity relative to clones in the reference population, associated with an overall eightfold increase in the mutation frequency. This observation suggests that individual infectious genomes of a quasispecies subjected to increased mutagenesis lose infectivity by their continuous mutagenic 'poisoning'. These results support the lethal defection model of virus extinction and the practical use of chemical mutagens as antiviral treatment. Even when extinction is not achieved, mutagenesis can decrease the infectivity of surviving virus, and facilitate their clearance by host immune responses or complementing antiviral approaches.
authors.affiliation: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1TN, UK.|Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
authors.forename: Armando
authors.initials: A
authors.lastname: Arias
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Isabel de Ávila
authors.affiliation: Division of Virology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.|Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Sanz-Ramos
authors.affiliation: Fachbereich Chemie, Philipps Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany.|Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Agudo
authors.affiliation: Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Escarmís
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.|Centro de Biología Molecular 'Severo Ochoa' (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain.
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D029544:Foot-and-Mouth Disease Virus / Q000145:classification / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D014644:Genetic Variation; D050296:Microbial Viability / Q000187:drug effects*; D009153:Mutagens / Q000378:metabolism*; D059645:Mutation Rate; D017354:Point Mutation; D012254:Ribavirin / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D009153:Mutagens; D012254:Ribavirin