The hepatitis C virus (HCV)
RNA polymerase (RdRp) may be a target of the drug
ribavirin, and it is an object of drug development. Independent isolates of any HCV subtype differ genetically by approximately 10%, but the effects of this variation on enzymatic activity and drug sensitivity are poorly understood. We proposed that
nucleotide use profiles (G/U ratio) among subtype 1b RdRps may reflect their use of
ribavirin. Here, we characterized how subtype 1b genetic variation affects
RNA polymerase activity and evaluated the G/U ratio as a surrogate for
ribavirin use during pegylated
interferon α and
ribavirin therapy. Genetic and biochemical variation in the RdRp was compared between responders who would be largely sensitive to
ribavirin and relapsers who would be mostly resistant. There were no consistent genetic differences between responder and relapser RdRps.
RNA polymerization,
RNA binding and primer usage varied widely among the RdRps, but these parameters did not differ significantly between the response groups. The G/U ratio among a set of subtype 1a RdRps increased rather than decreased following failed
therapy, as would be expected if it reflected
ribavirin use. Finally, RdRp activity was significantly associated with ALT levels. These data indicate that (i) current genetic approaches cannot predict
RNA polymerase behaviour, (ii) the G/U ratio is not a surrogate for
ribavirin use, (iii) RdRp activity may contribute to
liver disease by modulating viral
mRNA and
antigen levels, and (iv) drug candidates should be tested against multiple patient-derived
enzymes to ensure widespread efficacy even within a viral subtype.