Viruses from the Family Flaviviridae, including West Nile Virus, Dengue Virus and Hepatitis C Virus (HCV), are significant causes of morbidity and mortality, yet have few to no treatment options. Deoxyribonucleoside analogs form an important part of antiviral therapy for human immunodeficiency virus (HIV), but ribonucleoside analogs have been relatively unstudied for their potential to affect HCV or RNA viruses in general. We have determined conditions in which thiopurine nucleoside analogs inhibit a model Flaviviridae, Bovine Viral Diarrhea Virus (BVDV), in cell culture without cytotoxicity. Ribavirin, another purine analog, increases the efficacy of interferon treatment. Multiple mechanisms have been proposed for how ribavirin may act, but it remains unclear which mechanism(s) predominant. HCV positive transplant patients are often exposed to long-term immunosuppressive agents including thiopurines that also alter purine metabolism. Since these drugs share some, but not all of the mechanistic options for ribavirin, we will compare the effect of each on viral replication. The goal of this proposal is to extend these findings to HCV and determine the mechanism of action. Thiopurines will be tested for antiviral effect on the HCV replicon, and if they exert selective pressure on viral polymerases. Thiopurines will be tested for recognition, and utilization by the HCV and BVDV polymerase, which will aid us in designing more potent nucleosides. Finally we will further define the mechanism of this inhibition by looking at the size of purine pools and the effect of altering thiopurine metabolism on thiopurine's antiviral capacity. This proposal will determine the relative direct and indirect effect of thiopurines on RNA viral replication and the implications of that effect for the treatment of HCV patients with related purines such as ribavirin.
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