New Study Suggests Ribivarin Works By Causing Mutations:
". . . in our model RNA virus system, a surprisingly small increase (200-600%) in mutation rate produced a substantial antiviral effect."
from "The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen", Nature Medicine, December 2000 ( PDF of full report).
RNA viruses live as `quasispecies', creating extraordinary genetic diversity through mutation. It has been proposed that, because of this high mutation rate, RNA viruses exist on the threshold of `error catastrophe and a moderate increase in mutation rate can kill a RNA virus population by causing a `genetic meltdown'. An extrapolation of our sequencing data would indicate that, on average, each poliovirus genome (7,441 nucleotides long) synthesized after multiple rounds of replication inside an infected cell normally contains approximately two point mutations. In the presence of 1,000 M ribavirin, each poliovirus genome synthesized contains approximately 15 points mutations. Thus, in our model RNA virus system, a surprisingly small increase (200-600%) in mutation rate produced a substantial antiviral effect. Prolonged growth of human immunodeficiency virus (HIV) in the presence of mutagenic deoxyribonucleoside analogs inhibits multiplication of the virus.
In conclusion, the antiviral activity of ribavirin against poliovirus requires formation of RTP, this nucleotide is used by the viral RNA polymerase and the incorporated ribavirin is mutagenic. The ability of ribavirin monophosphate to inhibit IMPDH and thereby decrease cellular GTP pools probably serves to potentiate the mutagenic/antiviral effect by decreasing the concentration of `competitor' nucleotide and thereby increasing the frequency of ribavirin incorporation. This unified model for the mechanism of action of ribavirin predicts that mutagenic ribonucleosides that can be incorporated by viral RNA-dependent RNA polymerases may represent an important class of antiviral agents for the treatment of RNA virus infections.