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Hepatitis C virus diversity and evolution in the full open-reading frame during antiviral therapy.

Cannon NA, Donlin MJ, Fan X, Aurora R, Tavis JE, Virahep-C Study Gro - PLoS ONE (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: 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.

Trial registration: ClinicalTrials.gov NCT00038974.

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Related in: MedlinePlus

Unique amino acid variability among nonresponders and relapsers.Amino acid variations found exclusively in one response class but not in the other were compared between nonresponders and relapsers. Statistical significance of the difference in the number of variations was compared using the Mann-Whitney test. A) Pre-therapy. B) Post-therapy. The line represents the median value, and the box represents the 25–75% range. Whiskers represent samples within 1.5 box lengths, and the ° and * represent outliers between 1.5 and 3 box lengths and beyond 3 box lengths respectively.
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pone-0002123-g002: Unique amino acid variability among nonresponders and relapsers.Amino acid variations found exclusively in one response class but not in the other were compared between nonresponders and relapsers. Statistical significance of the difference in the number of variations was compared using the Mann-Whitney test. A) Pre-therapy. B) Post-therapy. The line represents the median value, and the box represents the 25–75% range. Whiskers represent samples within 1.5 box lengths, and the ° and * represent outliers between 1.5 and 3 box lengths and beyond 3 box lengths respectively.

Mentions: First, each sample was aligned against an external genotype 1a reference sequence [32], and positions of variation relative to the reference were identified for each sample. Variations were classified as unique to either relapsers or nonresponders if the variation was observed in one group of sequences but not in the other. In pre-therapy sequences, the polyproteins had similar numbers of unique variations in nonresponders and relapsers (Figure 2A). To determine if the variations were evenly distributed throughout the polyprotein, we compared the number of variations in each gene. Relapsers had significantly more unique variations in NS2 than the nonresponders by the Mann-Whitney test (p = 0.048). All other proteins had similar numbers of unique variations between the nonresponders and relapsers (p≥0.05). When the numbers of unique variations in the post-therapy polyproteins were compared, relapsers had more unique variations than nonresponders (p = 0.006) (Figure 2B). Examination of the individual genes revealed that there were more unique variations in the relapsers in E2 (p = 0.033), NS2 (p = 0.027), and NS3 (p = 0.045).


Hepatitis C virus diversity and evolution in the full open-reading frame during antiviral therapy.

Cannon NA, Donlin MJ, Fan X, Aurora R, Tavis JE, Virahep-C Study Gro - PLoS ONE (2008)

Unique amino acid variability among nonresponders and relapsers.Amino acid variations found exclusively in one response class but not in the other were compared between nonresponders and relapsers. Statistical significance of the difference in the number of variations was compared using the Mann-Whitney test. A) Pre-therapy. B) Post-therapy. The line represents the median value, and the box represents the 25–75% range. Whiskers represent samples within 1.5 box lengths, and the ° and * represent outliers between 1.5 and 3 box lengths and beyond 3 box lengths respectively.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2373758&req=5

pone-0002123-g002: Unique amino acid variability among nonresponders and relapsers.Amino acid variations found exclusively in one response class but not in the other were compared between nonresponders and relapsers. Statistical significance of the difference in the number of variations was compared using the Mann-Whitney test. A) Pre-therapy. B) Post-therapy. The line represents the median value, and the box represents the 25–75% range. Whiskers represent samples within 1.5 box lengths, and the ° and * represent outliers between 1.5 and 3 box lengths and beyond 3 box lengths respectively.
Mentions: First, each sample was aligned against an external genotype 1a reference sequence [32], and positions of variation relative to the reference were identified for each sample. Variations were classified as unique to either relapsers or nonresponders if the variation was observed in one group of sequences but not in the other. In pre-therapy sequences, the polyproteins had similar numbers of unique variations in nonresponders and relapsers (Figure 2A). To determine if the variations were evenly distributed throughout the polyprotein, we compared the number of variations in each gene. Relapsers had significantly more unique variations in NS2 than the nonresponders by the Mann-Whitney test (p = 0.048). All other proteins had similar numbers of unique variations between the nonresponders and relapsers (p≥0.05). When the numbers of unique variations in the post-therapy polyproteins were compared, relapsers had more unique variations than nonresponders (p = 0.006) (Figure 2B). Examination of the individual genes revealed that there were more unique variations in the relapsers in E2 (p = 0.033), NS2 (p = 0.027), and NS3 (p = 0.045).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.

ABSTRACT

Background: 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.

Methodology/principal findings: 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.

Conclusions/significance: 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.

Trial registration: ClinicalTrials.gov NCT00038974.

Show MeSH
Related in: MedlinePlus