Murine norovirus (MNV-1) exposure in vitro to the purine nucleoside analog Ribavirin increases quasispecies diversity

Timothy R. Julian, Joseph D. Baugher, Christine M. Rippinger, Rebecca Pinekenstein, Abimbola O. Kolawole, Thomas S. Mehoke, Christiane E. Wobus, Andrew B. Feldman, Fernando J Pineda, Kellogg Schwab

Research output: Contribution to journalArticle

Abstract

Ribavirin is a pharmaceutical antiviral used for the treatment of RNA virus infections including norovirus, hepatitis C virus, hepatitis E virus, Lassa virus, respiratory syncytial virus, and rhinovirus. Despite the drug's history and documented efficacy, the antiviral mechanism of Ribavirin remains unclear. Mechanisms proposed include depletion of the intracellular GTP pool, immunomodulatory effects, induction of error catastrophe, inhibition of viral polymerase activity, and/or inhibition of viral capping. In the present study, we leveraged deep sequencing data to demonstrate that Ribavirin increases murine norovirus (MNV-1) viral diversity. By serial passaging MNV-1 in RAW 264.7 cells for twenty generations in the presence of Ribavirin, we demonstrated statistically significant increases in both the number of unique haplotypes and the average pairwise difference (APD). Based on statistically significant differences in the probability of nucleotide mutations based on Roche 454 sequencing, we also demonstrated that single nucleotide substitutions are increased in the presence of Ribavirin. Finally, we demonstrated Ribavirin's impact on statistically significantly reducing the relative proportion of the dominant sequence within the quasispecies.

Original languageEnglish (US)
Pages (from-to)165-173
Number of pages9
JournalVirus Research
Volume211
DOIs
StatePublished - Jan 4 2016

Fingerprint

Purine Nucleosides
Norovirus
Ribavirin
Antiviral Agents
RNA Virus Infections
Lassa virus
Nucleotides
Hepatitis E virus
Rhinovirus
High-Throughput Nucleotide Sequencing
Respiratory Syncytial Viruses
Guanosine Triphosphate
Hepacivirus
Pharmaceutical Preparations
Haplotypes
In Vitro Techniques
History
Mutation

Keywords

  • MNV-1
  • Norovirus
  • Quasispecies
  • Ribavirin
  • Serial passaging

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases
  • Cancer Research

Cite this

Murine norovirus (MNV-1) exposure in vitro to the purine nucleoside analog Ribavirin increases quasispecies diversity. / Julian, Timothy R.; Baugher, Joseph D.; Rippinger, Christine M.; Pinekenstein, Rebecca; Kolawole, Abimbola O.; Mehoke, Thomas S.; Wobus, Christiane E.; Feldman, Andrew B.; Pineda, Fernando J; Schwab, Kellogg.

In: Virus Research, Vol. 211, 04.01.2016, p. 165-173.

Research output: Contribution to journalArticle

Julian, TR, Baugher, JD, Rippinger, CM, Pinekenstein, R, Kolawole, AO, Mehoke, TS, Wobus, CE, Feldman, AB, Pineda, FJ & Schwab, K 2016, 'Murine norovirus (MNV-1) exposure in vitro to the purine nucleoside analog Ribavirin increases quasispecies diversity', Virus Research, vol. 211, pp. 165-173. https://doi.org/10.1016/j.virusres.2015.10.016
Julian, Timothy R. ; Baugher, Joseph D. ; Rippinger, Christine M. ; Pinekenstein, Rebecca ; Kolawole, Abimbola O. ; Mehoke, Thomas S. ; Wobus, Christiane E. ; Feldman, Andrew B. ; Pineda, Fernando J ; Schwab, Kellogg. / Murine norovirus (MNV-1) exposure in vitro to the purine nucleoside analog Ribavirin increases quasispecies diversity. In: Virus Research. 2016 ; Vol. 211. pp. 165-173.
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