Analysis of sequence configurations of the ISDR, PKR-Binding domain, and V3 region as predictors of response to induction interferon-α and ribavirin therapy in chronic hepatitis C infection

Melissa D. Murphy, Hugo R. Rosen, Gail I. Marousek, Sunwen Chou

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54 Citations (Scopus)

Abstract

Interferon (IFN) and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection yields a sustained response rate of only ∼40%. Previous studies have linked IFN responsiveness to viral sequence variation in parts of the E2 and NS5A genes, but this remains controversial. We studied pretreatment sera from 28 subjects (23 with HCV genotype 1a) who received high-dose IFN induction followed by IFN-ribavirin combination therapy. Serum HCV sequences were amplified and compared from 14 responders with undetectable HCV RNA 24 weeks after therapy and 11 nonresponders (excluding three who dropped out of the study). Analysis included the E2 PKR eIF-2α phosphorylation homology domain (PePHD, codons 659-670), where the sequence was well conserved, and codons 2001-2420 of NS5A. In NS5A, the proposed PKR binding domain (codons 2209-2274), containing the putative IFN sensitivity determining region (ISDR, codons 2209-2248), showed too little variation among subjects to differentiate responders and nonresponders. NS5A codons 2356-2385 (which includes the V3 region) exhibited more variation. Here, six of 12 genotype 1a responders showed four or more amino acid changes from the prototype HCV-1 sequence, as compared with one of eight nonresponders, but this fell short of statistical significance (P = 0.16). NS5A sequences from posttreatment sera were examined in six nonresponders to look for selection of treatment-resistant viral subpopulations, but no consistent change was detected. In conclusion, our results indicate that the sequences of the ISDR, the PKR-binding domain, and the PePHD are unlikely to have predictive value for IFN treatment success in those infected with HCV genotype 1a. However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation.

Original languageEnglish (US)
Pages (from-to)1195-1205
Number of pages11
JournalDigestive Diseases and Sciences
Volume47
Issue number6
DOIs
StatePublished - 2002

Fingerprint

Ribavirin
Chronic Hepatitis C
Hepacivirus
Interferons
Sequence Analysis
Codon
Infection
Genotype
Therapeutics
Serum
Virus Diseases
Phosphorylation
RNA
Amino Acids
Genes

Keywords

  • Interferon sensitivity determining region (ISDR)
  • Phosphorylation homology domain
  • PKR binding domain
  • PKR-eIF-2α
  • V3 region

ASJC Scopus subject areas

  • Gastroenterology

Cite this

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title = "Analysis of sequence configurations of the ISDR, PKR-Binding domain, and V3 region as predictors of response to induction interferon-α and ribavirin therapy in chronic hepatitis C infection",
abstract = "Interferon (IFN) and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection yields a sustained response rate of only ∼40{\%}. Previous studies have linked IFN responsiveness to viral sequence variation in parts of the E2 and NS5A genes, but this remains controversial. We studied pretreatment sera from 28 subjects (23 with HCV genotype 1a) who received high-dose IFN induction followed by IFN-ribavirin combination therapy. Serum HCV sequences were amplified and compared from 14 responders with undetectable HCV RNA 24 weeks after therapy and 11 nonresponders (excluding three who dropped out of the study). Analysis included the E2 PKR eIF-2α phosphorylation homology domain (PePHD, codons 659-670), where the sequence was well conserved, and codons 2001-2420 of NS5A. In NS5A, the proposed PKR binding domain (codons 2209-2274), containing the putative IFN sensitivity determining region (ISDR, codons 2209-2248), showed too little variation among subjects to differentiate responders and nonresponders. NS5A codons 2356-2385 (which includes the V3 region) exhibited more variation. Here, six of 12 genotype 1a responders showed four or more amino acid changes from the prototype HCV-1 sequence, as compared with one of eight nonresponders, but this fell short of statistical significance (P = 0.16). NS5A sequences from posttreatment sera were examined in six nonresponders to look for selection of treatment-resistant viral subpopulations, but no consistent change was detected. In conclusion, our results indicate that the sequences of the ISDR, the PKR-binding domain, and the PePHD are unlikely to have predictive value for IFN treatment success in those infected with HCV genotype 1a. However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation.",
keywords = "Interferon sensitivity determining region (ISDR), Phosphorylation homology domain, PKR binding domain, PKR-eIF-2α, V3 region",
author = "Murphy, {Melissa D.} and Rosen, {Hugo R.} and Marousek, {Gail I.} and Sunwen Chou",
year = "2002",
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pages = "1195--1205",
journal = "American Journal of Digestive Diseases and Nutrition",
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T1 - Analysis of sequence configurations of the ISDR, PKR-Binding domain, and V3 region as predictors of response to induction interferon-α and ribavirin therapy in chronic hepatitis C infection

AU - Murphy, Melissa D.

AU - Rosen, Hugo R.

AU - Marousek, Gail I.

AU - Chou, Sunwen

PY - 2002

Y1 - 2002

N2 - Interferon (IFN) and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection yields a sustained response rate of only ∼40%. Previous studies have linked IFN responsiveness to viral sequence variation in parts of the E2 and NS5A genes, but this remains controversial. We studied pretreatment sera from 28 subjects (23 with HCV genotype 1a) who received high-dose IFN induction followed by IFN-ribavirin combination therapy. Serum HCV sequences were amplified and compared from 14 responders with undetectable HCV RNA 24 weeks after therapy and 11 nonresponders (excluding three who dropped out of the study). Analysis included the E2 PKR eIF-2α phosphorylation homology domain (PePHD, codons 659-670), where the sequence was well conserved, and codons 2001-2420 of NS5A. In NS5A, the proposed PKR binding domain (codons 2209-2274), containing the putative IFN sensitivity determining region (ISDR, codons 2209-2248), showed too little variation among subjects to differentiate responders and nonresponders. NS5A codons 2356-2385 (which includes the V3 region) exhibited more variation. Here, six of 12 genotype 1a responders showed four or more amino acid changes from the prototype HCV-1 sequence, as compared with one of eight nonresponders, but this fell short of statistical significance (P = 0.16). NS5A sequences from posttreatment sera were examined in six nonresponders to look for selection of treatment-resistant viral subpopulations, but no consistent change was detected. In conclusion, our results indicate that the sequences of the ISDR, the PKR-binding domain, and the PePHD are unlikely to have predictive value for IFN treatment success in those infected with HCV genotype 1a. However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation.

AB - Interferon (IFN) and ribavirin combination therapy for chronic hepatitis C virus (HCV) infection yields a sustained response rate of only ∼40%. Previous studies have linked IFN responsiveness to viral sequence variation in parts of the E2 and NS5A genes, but this remains controversial. We studied pretreatment sera from 28 subjects (23 with HCV genotype 1a) who received high-dose IFN induction followed by IFN-ribavirin combination therapy. Serum HCV sequences were amplified and compared from 14 responders with undetectable HCV RNA 24 weeks after therapy and 11 nonresponders (excluding three who dropped out of the study). Analysis included the E2 PKR eIF-2α phosphorylation homology domain (PePHD, codons 659-670), where the sequence was well conserved, and codons 2001-2420 of NS5A. In NS5A, the proposed PKR binding domain (codons 2209-2274), containing the putative IFN sensitivity determining region (ISDR, codons 2209-2248), showed too little variation among subjects to differentiate responders and nonresponders. NS5A codons 2356-2385 (which includes the V3 region) exhibited more variation. Here, six of 12 genotype 1a responders showed four or more amino acid changes from the prototype HCV-1 sequence, as compared with one of eight nonresponders, but this fell short of statistical significance (P = 0.16). NS5A sequences from posttreatment sera were examined in six nonresponders to look for selection of treatment-resistant viral subpopulations, but no consistent change was detected. In conclusion, our results indicate that the sequences of the ISDR, the PKR-binding domain, and the PePHD are unlikely to have predictive value for IFN treatment success in those infected with HCV genotype 1a. However, the finding of greater variability among treatment responders in the carboxy end of NS5A suggests that the V3 region merits further investigation.

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