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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

Protein distance in nonresponders, relapsers, and responder pre-therapy sequences.Comparison of the protein distances in three-phenotypes of patients.
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pone-0002123-g005: Protein distance in nonresponders, relapsers, and responder pre-therapy sequences.Comparison of the protein distances in three-phenotypes of patients.

Mentions: Finally, the inter-patient protein distance of pre-therapy sequences among nonresponders, relapsers, and responders was compared to the distance among sustained viral responders to antiviral therapy in the Virahep-C study [32] to determine how the patterns observed in nonresponders and relapsers compared to sequences that were responsive to pegylated interferon α and ribavirin therapy. The intra-group distances of responders were plotted in Figure 5 along with the nonresponders and relapsers. Two patterns were most common. First, in the polyprotein, core, E2, NS3, NS4B, and NS5B, the responders had the highest distances between samples, relapsers were intermediate, and nonresponders had the lowest distances. The second pattern was observed in E1, P7, NS4A, and NS5A, where the relapsers were similar to the nonresponders but the responders had higher distances. The single exception to these two patterns was in NS2, where the relapsers had distances similar to the responders but the nonresponders were significantly lower. When analyzed using ANOVA, there were differences in all proteins (p<0.005). These data indicate that a spectrum of variability exists among the response classes, with responders being the most variable, relapsers being intermediate, and nonresponders being the least variable. The most notable exception to this general pattern was NS2, where relapsers resembled responders.


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)

Protein distance in nonresponders, relapsers, and responder pre-therapy sequences.Comparison of the protein distances in three-phenotypes of patients.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002123-g005: Protein distance in nonresponders, relapsers, and responder pre-therapy sequences.Comparison of the protein distances in three-phenotypes of patients.
Mentions: Finally, the inter-patient protein distance of pre-therapy sequences among nonresponders, relapsers, and responders was compared to the distance among sustained viral responders to antiviral therapy in the Virahep-C study [32] to determine how the patterns observed in nonresponders and relapsers compared to sequences that were responsive to pegylated interferon α and ribavirin therapy. The intra-group distances of responders were plotted in Figure 5 along with the nonresponders and relapsers. Two patterns were most common. First, in the polyprotein, core, E2, NS3, NS4B, and NS5B, the responders had the highest distances between samples, relapsers were intermediate, and nonresponders had the lowest distances. The second pattern was observed in E1, P7, NS4A, and NS5A, where the relapsers were similar to the nonresponders but the responders had higher distances. The single exception to these two patterns was in NS2, where the relapsers had distances similar to the responders but the nonresponders were significantly lower. When analyzed using ANOVA, there were differences in all proteins (p<0.005). These data indicate that a spectrum of variability exists among the response classes, with responders being the most variable, relapsers being intermediate, and nonresponders being the least variable. The most notable exception to this general pattern was NS2, where relapsers resembled responders.

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