Lethal mutagenesis of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV).
Passage of the prototypic arenavirus lymphocytic choriomenigitis virus (LCMV) in cultured cells in the presence of the mutagenic agent 5-fluorouracil (FU) resulted in efficient and systematic virus extinction under conditions that did not significantly affect cell survival. FU-mediated extinction of LCMV was associated with 3.6- to 10-fold increases in the mutation frequencies for the three viral genes examined, but with only very modest effects on virus replication and transcription during a single round of infection. Likewise, FU did not affect expression of a LCMV minigenome. In contrast, the well documented antiviral effect of ribavirin against LCMV was not associated with significant increases in virus mutation frequencies, but rather with a dramatic inhibition of both viral RNA synthesis and LCMV minigenome expression. Mutagen induced viral extinction has been recently reported for positive strand RNA viruses polio and foot-and-mouth disease, and the lentivirus HIV-1. Our findings indicate that lethal mutagenesis can be effective also against LCMV, a negative strand RNA virus. Moreover, FU treatment prevented the establishment of LCMV persistent infection in mice deficient in B and T cells, suggesting the feasibility in vivo of lethal mutagenesis as a novel antiviral strategy.
Ruiz-Jarabo
Carmen M
CM
Centro de Biologia Molecular Severo Ochoa (CSIC, UAM), Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Ly
Calvin
C
Domingo
Esteban
E
de la Torre
Juan Carlos
JC
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001117:Arenaviridae Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000172:deficiency; D005472:Fluorouracil / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis / Q000187:drug effects*; D012367:RNA, Viral / Q000032:analysis / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000172:deficiency; D012254:Ribavirin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004268:DNA-Binding Proteins; D012367:RNA, Viral; C499308:Rag2 protein, mouse; D017471:Receptors, Interferon; C064655:V(D)J recombination activating protein 2; D012254:Ribavirin; D005472:Fluorouracil