RESEARCH ARTICLE XRN1 Stalling in the 5 ’ UTR of Hepatitis C Virus and Bovine Viral Diarrhea Virus Is Associated with Dysregulated Host mRNA Stability

We demonstrate that both Hepatitis C virus (HCV) and Bovine Viral Diarrhea virus (BVDV) contain regions in their 5 ’ UTRs that stall and repress the enzymatic activity of the cellular 5’-3 ’ exoribonuclease XRN1, resulting in dramatic changes in the stability of cellular mRNAs. We used biochemical assays, virus infections, and transfection of the HCV and BVDV 5 ’ untranslated regions in the absence of other viral gene products to directly demon-strate the existence and mechanism of this novel host-virus interaction. In the context of HCV infection, we observed globally increased stability of mRNAs resulting in significant in-creases in abundance of normally short-lived mRNAs encoding a variety of relevant onco-genes and angiogenesis factors. These findings suggest that non-coding regions from multiple genera of the Flaviviridae interfere with XRN1 and impact post-transcriptional pro-cesses, causing global dysregulation of cellular gene expression which may promote cell growth and pathogenesis. Author Summary Understanding how a persistent virus like Hepatitis C Virus (HCV) interfaces with the cel