Resistance of high fitness hepatitis C virus to lethal mutagenesis

Viral fitness quantifies the degree of virus adaptation to a given environment. How viral fitness can influence the mutant spectrum complexity of a viral quasispeciessubjected to lethal mutagenesis has not been investigated. Here we document that two high fitness hepatitis C virus populations display higher resistance to themutagenic nucleoside analogues favipiravir and ribavirin than their parental, low fitness HCV. All populations, however, exhibited a mutation transition biasindicative of active mutagenesis. Resistance to the analogues was associated with a limited expansion of mutant spectrum complexity, as evidenced by severaldiversity indices used to characterize mutant spectra. The results are consistent with a replicative site-drug competition mechanism that was previously proposed forHCV fitness-associated resistance to non-mutagenic inhibitors. Other alternative, non-mutually exclusive mechanisms are considered. The results introduce viralfitness as a relevant parameter to evaluate the response of viruses to lethal mutagenesis, with implications for antiviral designs.