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Published on: July 16, 2012
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.
Abstract:
Interferon treatment of chronic hepatitis C virus infection is successful in a minority of patients. The sequence of the interferon sensitivity determining region (ISDR) of the NS5A protein may determine the outcome of therapy in patients infected with HCV genotype 1. To determine whether IFN treatment caused selection of ISDR quasispecies and whether sequences bearing the putative IFN-resistance motif (HCV-J sequence) were selected, we examined amino acid changes in the ISDR in patients with HCV of different genotypes with and without therapy. We found that the ISDR sequence was highly variable and variability was greatest in patients with HCV of genotype 1. IFN treatment was found to exert a selection pressure on ISDR quasispecies, but the putative interferon-resistant variant was not enriched in patients of any genotype. Hence factors other than the sequence of the ISDR region played a role in the IFN resistance of these patients.
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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