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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 pre- and post-therapy samples.Comparison of pre- and post-therapy protein distances in A) nonresponders and B) relapsers. Statistical significance was determined using the Mann-Whitney test.
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pone-0002123-g004: Protein distance in pre- and post-therapy samples.Comparison of pre- and post-therapy protein distances in A) nonresponders and B) relapsers. Statistical significance was determined using the Mann-Whitney test.

Mentions: We next asked whether the greater differences between nonresponders and relapsers in the post-therapy analysis were due to changes in sequences from the nonresponders, relapsers, or both by comparing the pre- versus post-therapy protein distances among the nonresponders and relapsers (Figure 4). The protein distance among nonresponders declined significantly in core (p = 0.006) and NS4A (p = 0.027) in the nonresponders during therapy, while the other proteins did not change significantly. Relapsers had a different pattern. Core (p = 0.046), E1 (p = 0.006), NS4B (p = 0.023), and NS5A (p = 0.041) had statistically significant increases in protein distance during therapy, and many of the other proteins, including the polyprotein, had increases that did not reach statistical significance. Overall, protein distances declined slightly in nonresponders during therapy, whereas they increased substantially in relapsers.


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 pre- and post-therapy samples.Comparison of pre- and post-therapy protein distances in A) nonresponders and B) relapsers. Statistical significance was determined using the Mann-Whitney test.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0002123-g004: Protein distance in pre- and post-therapy samples.Comparison of pre- and post-therapy protein distances in A) nonresponders and B) relapsers. Statistical significance was determined using the Mann-Whitney test.
Mentions: We next asked whether the greater differences between nonresponders and relapsers in the post-therapy analysis were due to changes in sequences from the nonresponders, relapsers, or both by comparing the pre- versus post-therapy protein distances among the nonresponders and relapsers (Figure 4). The protein distance among nonresponders declined significantly in core (p = 0.006) and NS4A (p = 0.027) in the nonresponders during therapy, while the other proteins did not change significantly. Relapsers had a different pattern. Core (p = 0.046), E1 (p = 0.006), NS4B (p = 0.023), and NS5A (p = 0.041) had statistically significant increases in protein distance during therapy, and many of the other proteins, including the polyprotein, had increases that did not reach statistical significance. Overall, protein distances declined slightly in nonresponders during therapy, whereas they increased substantially in relapsers.

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