Abstract
Lethal mutagenesis is an antiviral approach that consists in extinguishing a virus by an excess of mutations acquired during replication in the presence of a mutagen. Here we show that favipiravir (T-705) is a potent mutagenic agent for hepatitis C virus (HCV) during its replication in human hepatoma cells. T-705 leads to an excess of G → A and C → U transitions in the mutant spectrum of preextinction HCV populations. Infectivity decreased significantly in the presence of concentrations of T-705 which are 2- to 8-fold lower than its cytotoxic concentration 50 (CC50). Passaging the virus five times in the presence of 400 μM T-705 resulted in virus extinction. Since T-705 has undergone advanced clinical trials for approval for human use, the results open a new approach based on lethal mutagenesis to treat hepatitis C virus infections. If proven effective for HCV in vivo, this new anti-HCV agent may be useful in patient groups that fail current therapeutic regimens.
Highlights
Lethal mutagenesis is an antiviral approach consisting of achieving viral extinction by an excess of mutations [1,2,3,4,5,6]
T-705 is a potent inhibitor of hepatitis C virus (HCV) during replication in Huh-7.5 cells that can lead to virus extinction
In the present report we have shown that favipiravir (T-705) is a potent inhibitor of HCV replication in Huh-7.5 cells, with a therapeutic index (TI) value of 116.9 which is seven to nine times the value obtained previously for ribavirin in two independent determinations in the same virus-host system (TI = 12.8 [42]; TI = 15.6 [55])
Summary
Lethal mutagenesis is an antiviral approach consisting of achieving viral extinction by an excess of mutations [1,2,3,4,5,6]. It is an application of the error threshold relationship of quasispecies theory that can be applied to finite populations of viruses in changing fitness landscapes [7]. We were interested in exploring lethal mutagenesis for the treatment of HCV infections, based on the evidence that ribavirin (1-β-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide), an important component of several anti-HCV therapies, might be exerting its antiviral action partly through lethal mutagenesis [8,9]. Effective antiviral lethal mutagenesis therapy will require additional agents that mutagenize the virus and not the cells, and provide an advantage over standard non-mutagenic inhibitors and their combinations.
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