Ribavirin Reveals a Lethal Threshold of Allowable Mutation Frequency for Hantaan Virus

• DOI: 10.1128/jvi.00874-07
• Publication Date: 2007-08-16T00:18:25Z
• Authors: Dong-Hoon Chung; Yanjie Sun; William B. Parker; Jeffrey B. Arterburn; Al Bartolucci; Colleen B. Jonsson
• Keywords: Hantaan virus

The broad spectrum of antiviral activity ribavirin (RBV) lies in its ability to inhibit IMP dehydrogenase, which lowers cellular GTP. However, RBV can act as a potent mutagen for some RNA viruses. Previously we have shown lack correlation between and GTP repression Hantaan virus (HTNV) evidence RBV's promote error-prone replication. To further explore the mechanism RBV, levels, specific infectivity, and/or mutation frequency was measured presence mycophenolic acid (MPA), selenazofurin, or tiazofurin. While all four drugs resulted decrease levels infectious virus, only increased viral (vRNA). MPA, however, could enhance mutagenic effect, suggests distinct mechanisms action each. Therefore, simple drop does not drive observed action, made comprehensive analysis over several concentrations. Of importance, that population reached threshold after did correlate with dose-dependent level vRNA, PFU, [RTP]/[GTP] (where RTP is ribavirin-5'-triphosphate) these same concentrations RBV. Modeling relationship drug concentration showed an asymptotic at this point. After threshold, approximately 57% cDNA identical wild type. These studies revealed lethal observe complete loss quasispecies structure wild-type genome, although extinction HTNV.