Mutations induced in the NS5B gene of bovine viral diarrhea virus by antiviral treatment convey resistance to the compound

• Genomic sequencing was performed on resistant isolates obtained after antiviral treatment.
• A common mutation was found in the NS5B region of the genome in all resistant isolates.
• Two isolates had an additional mutation in the same region.
• Observed mutations did not largely alter growth curves for mutant isolates.
• Compound appears to act by binding to the region of NS5B exhibiting the mutations.

Bovine viral diarrhea virus (BVDV) is a widespread bovine pathogen for which there is no specific therapeutic agent. A previous study using 2-(2-benzimidazolyl)-5-[4-(2-imidazolino)phenyl]furan dihydrochloride (DB772) to treat calves persistently infected with BVDV resulted in a decrease in the viral load of infected calves but treatment resulted in the rapid selection of drug-resistant mutant isolates. In this article we describe three mutations found in the mutant isolates associated with in vivo and in vitro resistance to DB772. All three mutations are found in the NS5B which functions as the RNA-dependent-RNA-polymerase during viral replication. Growth curves for the mutant isolates were not largely different from those of wild-type isolates when cultured in the absence of DB772. Thus, DB772 appears to act by binding to the specified domain but binding is disrupted or inhibited by the described mutation.