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Mutations in HCV non-structural genes do not contribute to resistance to nitazoxanide in replicon-containing cells

Changsuek Yon1, Prasanth Viswanathan, Jean-François Rossignol

  • 1Georgetown University Medical Center, Department of Microbiology and Immunology, Washington, DC, USA.

Antiviral Research
|June 28, 2011
PubMed

Insights

Hepatitis C virus (HCV) resistance to nitazoxanide (NTZ) is not caused by viral mutations. Instead, resistance and NTZ

Area of Science:

  • Virology
  • Hepatology
  • Drug Resistance

Background:

  • Nitazoxanide (NTZ) demonstrates significant antiviral efficacy against Hepatitis C virus (HCV) in cellular models.
  • Previous studies indicated the selection of NTZ-resistant HCV cell lines, but the mechanism of resistance remained unclear.

Purpose of the Study:

  • To investigate the molecular basis of HCV resistance to nitazoxanide (NTZ).
  • To determine if viral mutations or cellular factors contribute to NTZ resistance in HCV.

Main Methods:

  • Sequencing of full-length HCV replicons from NTZ-resistant and parental cell lines.
  • Introduction of specific 5'-UTR mutations into wild-type HCV replicons.
  • Transfection experiments using whole cell RNA from cured cell lines and various replicon constructs.
  • Enzymatic assays to assess the activity of NTZ's active metabolite (TIZ) against HCV viral enzymes.

Main Results:

  • No common mutations in HCV non-structural genes or 3'-UTR were identified in resistant strains.
  • A cluster of mutations in the 5'-UTR was observed in resistant replicons, but individual mutations reduced replication without conferring resistance.
  • Transfection experiments demonstrated that the NTZ-resistance phenotype could be transferred via cellular RNA, independent of viral mutations.
  • The active metabolite of NTZ, TIZ, showed no direct inhibitory activity against HCV polymerase, protease, or helicase in vitro.

Conclusions:

  • HCV resistance to nitazoxanide is not mediated by mutations within the viral genome.
  • The antiviral activity of NTZ and HCV resistance to it likely involve interactions with host cellular targets.
  • These findings suggest a host-dependent mechanism for NTZ's action against HCV.

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