title: Lethal mutagenesis of foot-and-mouth disease virus involves shifts in sequence space.
abstract: Lethal mutagenesis or virus transition into error catastrophe is an antiviral strategy that aims at extinguishing a virus by increasing the viral mutation rates during replication. The molecular basis of lethal mutagenesis is largely unknown. Previous studies showed that a critical substitution in the foot-and-mouth disease virus (FMDV) polymerase was sufficient to allow the virus to escape extinction through modulation of the transition types induced by the purine nucleoside analogue ribavirin. This substitution was not detected in mutant spectra of FMDV populations that had not replicated in the presence of ribavirin, using standard molecular cloning and nucleotide sequencing. Here we selectively amplify and analyze low-melting-temperature cDNA duplexes copied from FMDV genome populations passaged in the absence or presence of ribovirin Hypermutated genomes with high frequencies of A and U were present in both ribavirin -treated and untreated populations, but the major effect of ribavirin mutagenesis was to accelerate the occurrence of AU-rich mutant clouds during the early replication rounds of the virus. The standard FMDV quasispecies passaged in the absence of ribavirin included the salient transition-modulating, ribavirin resistance mutation, whose frequency increased in populations treated with ribavirin. Thus, even nonmutagenized FMDV quasispecies include a deep, mutationally biased portion of sequence space, in support of the view that the virus replicates close to the error threshold for maintenance of genetic information.
authors.affiliation: Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, 28049 Madrid, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Perales
authors.forename: Michel
authors.initials: M
authors.lastname: Henry
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
authors.forename: Simon
authors.initials: S
authors.lastname: Wain-Hobson
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vartanian
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D006224:Cricetinae; D004261:DNA Replication; D024882:Drug Resistance, Viral; D029544:Foot-and-Mouth Disease Virus / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D005804:Genes, Lethal; D016679:Genome, Viral; D007668:Kidney / Q000166:cytology; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology*; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D012333:RNA, Messenger; D012367:RNA, Viral; D012254:Ribavirin