Selection of HCV NS5A quasispecies during IFN therapy in patients with chronic HCV

M Paterson1, C Laxton, R D Goldin

  • 1Liver Centre, Imperial College School of Medicine at St Mary's, St Mary's Hospital. London, UK.

Insights

Interferon treatment for chronic hepatitis C virus (HCV) infection shows limited success. While interferon (IFN) therapy selects for ISDR quasispecies, the specific HCV-J sequence linked to resistance was not enriched, suggesting other factors influence treatment outcomes.

Area of Science:

  • Hepatology
  • Virology
  • Immunology

Background:

  • Hepatitis C virus (HCV) infection is a significant global health concern.
  • Interferon (IFN) therapy is a treatment for chronic HCV infection, but its success rate is low.
  • The interferon sensitivity determining region (ISDR) within the NS5A protein of HCV genotype 1 is hypothesized to influence treatment outcomes.

Purpose of the Study:

  • To investigate whether IFN treatment selects for specific ISDR quasispecies in patients with HCV.
  • To determine if the putative IFN-resistance motif (HCV-J sequence) is enriched following IFN therapy.
  • To analyze amino acid changes in the ISDR across different HCV genotypes with and without IFN treatment.

Main Methods:

  • Analysis of amino acid sequences within the ISDR of the NS5A protein.
  • Comparison of ISDR sequences in patients with and without interferon therapy.
  • Examination of sequence variability and selection pressures across different HCV genotypes.

Main Results:

  • The ISDR sequence exhibits high variability, particularly in patients with HCV genotype 1.
  • IFN treatment exerts a selection pressure on ISDR quasispecies.
  • The putative IFN-resistant HCV-J variant was not found to be enriched in patients of any genotype studied.

Conclusions:

  • The sequence variability within the ISDR of HCV is significant.
  • IFN treatment influences the quasispecies composition of the ISDR.
  • Factors beyond the ISDR sequence are likely responsible for interferon resistance in HCV patients.

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