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Evidence for sequence selection within the non-structural 5A gene of hepatitis C virus type 1b during unsuccessful

M Gerotto1, F Dal Pero, D G Sullivan

  • 1Department of Clinical and Experimental Medicine, University of Padua, Italy.

Journal of Viral Hepatitis
|December 22, 1999
PubMed

Insights

Hepatitis C virus (HCV) resistance to interferon-alpha (IFN-alpha) therapy may involve the NS5A gene

Area of Science:

  • Virology
  • Hepatology
  • Genetics

Background:

  • Hepatitis C virus (HCV) infection is a global health concern.
  • Interferon-alpha (IFN-alpha) therapy is a treatment for HCV, but resistance can occur.
  • Genetic factors within the HCV NS5A gene, specifically the ISDR, are implicated in IFN-alpha resistance.

Purpose of the Study:

  • To investigate the role of the ISDR within the NS5A gene in HCV 1b resistance to IFN-alpha therapy.
  • To determine if 'resistant' ISDR types are selected during unsuccessful IFN-alpha treatment.
  • To analyze the evolution of NS5A quasispecies and ISDR sequences in non-responding patients.

Main Methods:

  • Analysis of NS5A quasispecies evolution using clonal frequency analysis.
  • Determination of ISDR sequences by nucleotide sequencing.
  • Study involved 11 patients with no virological response to two consecutive IFN-alpha therapy cycles.

Main Results:

  • Patients with IFN-alpha resistance exhibited homogeneous ISDR quasispecies with 'resistant-' or 'intermediate-' type sequences.
  • Retreatment with IFN-alpha led to further selection of a homogeneous viral population.
  • 10 out of 11 patients developed a single HCV variant with minimal ISDR mutations after retreatment.

Conclusions:

  • IFN-alpha treatment and retreatment in non-responders selects for a homogeneous viral population with conserved ISDR motifs.
  • The ISDR motif appears to be a significant factor in HCV 1b resistance to IFN-alpha.
  • These findings support the genetic basis of IFN-alpha resistance in HCV 1b infections.

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