Error-prone replication of West Nile virus caused by ribavirin.
Ribavirin has been reported to cause error-prone replication and viral extinction in RNA viruses. The antiviral activity of ribavirin against West Nile virus (WNV) was evaluated in various cell lines to select a model in which mutagenic effects could be studied. The antiviral activity was greatest in HeLa cells as compared to CV-1, L929, Vero, or MA-104 cells. WNV was also passaged sequentially in cell monolayers treated with ribavirin to determine whether cumulative mutations could lead to viral extinction in these cell lines. The virus was abrogated in HeLa cells after 4 passages, while high viral titers persisted after many passages in other cells. A molecular clone of WNV was propagated in HeLa cells treated with 15 microg/mL ribavirin, and sequencing of viral genome segments revealed significant increases in transition mutations, demonstrating that ribavirin induced error-prone replication. The relative infectivity of viral RNA synthesized in the presence of ribavirin was shown to be reduced compared with untreated controls. These data support the hypothesis that error catastrophe is one of the modes of action for ribavirin against WNV.
Day
Craig W
CW
Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, 4700 Old Main Hill, Utah State University, Logan, UT 84322-4700, USA.
Smee
Donald F
DF
Julander
Justin G
JG
Yamshchikov
Vladimir F
VF
Sidwell
Robert W
RW
Morrey
John D
JD
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D012367:RNA, Viral / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology* / Q000633:toxicity; D017422:Sequence Analysis, DNA; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*; D014902:West Nile virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
D000998:Antiviral Agents; D012367:RNA, Viral; D012254:Ribavirin