Dataset Information

Genetic diversity of the hepatitis C virus: impact and issues in the antiviral therapy.

ABSTRACT: The hepatitis C Virus (HCV) presents a high degree of genetic variability which is explained by the combination of a lack of proof reading by the RNA dependant RNA polymerase and a high level of viral replication. The resulting genetic polymorphism defines a classification in clades, genotypes, subtypes, isolates and quasispecies. This diversity is known to reflect the range of responses to Interferon therapy. The genotype is one of the predictive parameters currently used to define the antiviral treatment strategy and the chance of therapeutic success. Studies have also reported the potential impact of the viral genetic polymorphism in the outcome of antiviral therapy in patients infected by the same HCV genotype. Both structural and non structural genomic regions of HCV have been suggested to be involved in the Interferon pathway and the resistance to antiviral therapy. In this review, we first detail the viral basis of HCV diversity. Then, the HCV genetic regions that may be implicated in resistance to therapy are described, with a focus on the structural region encoded by the E2 gene and the non-structural genes NS3, NS5A and NS5B. Both mechanisms of the Interferon resistance and of the new antiviral drugs are described in this review.

SUBMITTER: Le Guillou-Guillemette H

PROVIDER: S-EPMC4146759 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Genetic diversity of the hepatitis C virus: impact and issues in the antiviral therapy.

Le Guillou-Guillemette H H Vallet S S Gaudy-Graffin C C Payan C C Pivert A A Goudeau A A Lunel-Fabiani F F

World journal of gastroenterology 20070501 17

The hepatitis C Virus (HCV) presents a high degree of genetic variability which is explained by the combination of a lack of proof reading by the RNA dependant RNA polymerase and a high level of viral replication. The resulting genetic polymorphism defines a classification in clades, genotypes, subtypes, isolates and quasispecies. This diversity is known to reflect the range of responses to Interferon therapy. The genotype is one of the predictive parameters currently used to define the antivira ...[more]

PMID: 17552024

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Project description:Pegylated interferon plus ribavirin therapy for hepatitis C virus (HCV) fails in approximately half of genotype 1 patients. Treatment failure occurs either by nonresponse (minimal declines in viral titer) or relapse (robust initial responses followed by rebounds of viral titers during or after therapy). HCV is highly variable genetically. To determine if viral genetic differences contribute to the difference between response and relapse, we examined the inter-patient genetic diversity and mutation pattern in the full open reading frame HCV genotype 1a consensus sequences.Pre- and post-therapy sequences were analyzed for 10 nonresponders and 10 relapsers from the Virahep-C clinical study. Pre-therapy interpatient diversity among the relapsers was higher than in the nonresponders in the viral NS2 and NS3 genes, and post-therapy diversity was higher in the relapsers for most of HCV's ten genes. Pre-therapy diversity among the relapsers was intermediate between that of the non-responders and responders to therapy. The average mutation rate was just 0.9% at the amino acid level and similar numbers of mutations occurred in the nonresponder and relapser sequences, but the mutations in NS2 of relapsers were less conservative than in nonresponders. Finally, the number and distribution of regions under positive selection was similar between the two groups, although the nonresponders had more foci of positive selection in E2.The HCV sequences were unexpectedly stable during failed antiviral therapy, both nonresponder and relapser sequences were under selective pressure during therapy, and variation in NS2 may have contributed to the difference in response between the nonresponder and relapser groups. These data support a role for viral genetic variability in determining the outcome of anti-HCV therapy, with those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy.ClinicalTrials.gov NCT00038974.

Dataset Information

Genetic diversity of the hepatitis C virus: impact and issues in the antiviral therapy.

Publications

Genetic diversity of the hepatitis C virus: impact and issues in the antiviral therapy.

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