Abstract
Bovine viral diarrhea virus (BVDV) is the prototype Pestivirus. BVDV infection is distributed worldwide and causes serious problems for the livestock industry. The thiosemicarbazone of 5,6-dimethoxy-1-indanone (TSC) is a non-nucleoside polymerase inhibitor (NNI) of BVDV. All TSC-resistant BVDV variants (BVDV-TSCr T1–5) present an N264D mutation in the NS5B gene (RdRp) whereas the variant BVDV-TSCr T1 also presents an NS5B A392E mutation. In the present study, we carried out twenty passages of BVDV-TSCr T1–5 in MDBK cells in the absence of TSC to evaluate the stability of the resistance. The viral populations obtained (BVDV R1–5) remained resistant to the antiviral compound and conserved the mutations in NS5B associated with this phenotype. Along the passages, BVDV R2, R3 and R5 presented a delay in the production of cytopathic effect that correlated with a decrease in cell apoptosis and intracellular accumulation of viral RNA. The complete genome sequences that encode for NS2 to NS5B, Npro and Erns were analyzed. Additional mutations were detected in the NS5B of BVDV R1, R3 and R4. In both BVDV R2 and R3, most of the mutations found were localized in NS5A, whereas in BVDV R5, the only mutation fixed was NS5A V177A. These results suggest that mutations in NS5A could alter BVDV cytopathogenicity. In conclusion, the stability of the resistance to TSC may be due to the fixation of different compensatory mutations in each BVDV-TSCr. During their replication in a TSC-free medium, some virus populations presented a kind of interaction with the host cell that resembled a persistent infection: decreased cytopathogenicity and viral genome synthesis. This is the first report on the stability of antiviral resistance and on the evolution of NNI-resistant BVDV variants. The results obtained for BVDV-TSCr could also be applied for other NNIs.
Highlights
Bovine viral diarrhea virus (BVDV), along with classical swine fever virus and border disease virus, is a member of the genus Pestivirus
A previous work has shown that BVDV variants that carry the NS5B N264D mutation, which confers resistance to TSC and to other non-nucleoside polymerase inhibitors (NNI) [49], [50], present a replication disadvantage when competing with the wild-type virus in an antiviral-free environment [51]
The replication of BVDVTSCr in the absence of TSC led to the fixation of different mutations along the NS region that could compensate for the reduced fitness caused by the N264D mutation and confer some stability to the TSC-resistant phenotype
Summary
Bovine viral diarrhea virus (BVDV), along with classical swine fever virus and border disease virus, is a member of the genus Pestivirus. This genus belongs to the family Flaviviridae, which includes the genera Hepacivirus (hepatitis C virus) and Flavivirus (yellow fever virus, Dengue fever virus and West Nile virus). In Argentina, the prevalence of BVDV antibodies in adult cattle is around 70% [3], [4]. BVDV infections lead to a reduction in milk production, lower conception rates, respiratory disorders and death of the animals that acquire the acute infection, causing serious economic losses for the livestock industry. Fetal infection leads to persistently infected cattle, which are generally smaller, are more susceptible to other infections and eventually develop a lethal mucosal disease
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