Possible molecular mechanism of the relationship between NS5B polymorphisms and early clearance of hepatitis C virus during interferon plus ribavirin treatment

Mitsuyasu Nakamura, Hidetsugu Saito, Masanori Ikeda, Shinichiro Tada, Naoki Kumagai, Nobuyuki Kato, Kunitada Shimotohno, Toshifumi Hibi

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

We previously reported the relationship between viral polymerase polymorphisms and the initial decline in viral load induced by interferon-α and ribavirin therapy in genotype 1b-related chronic hepatitis C patients. The presence of E124K and I85V of NS5B was closely associated with viral clearance at 8 weeks of treatment. The aim of this study was to investigate the mechanisms by which this polymorphism of NS5B protein affects early viral clearance. We used a replicon system derived from strain O, genotype 1b virus. Three mutants (V85I), (K124E), and (V85I/K124E) were introduced to the replicon. OR6c, a derivative of HuH7 cells, was transfected with the replicon including a luciferase reporter gene. Luciferase activities were measured 72 hr post-transfection. All three mutants showed higher luciferase activity than that of the wild type, and the V85I mutant showed the highest activity. This result was also confirmed by neomycin gene-containing replicons with same mutations. All replicons were down-regulated by ribavirin, but the level of reduction in the V85I mutant was the lowest. Our results suggested that this mutation at least partly contributes to resistance to early viral clearance during interferon and ribavirin combination therapy.

Original languageEnglish
Pages (from-to)632-639
Number of pages8
JournalJournal of Medical Virology
Volume80
Issue number4
DOIs
Publication statusPublished - 2008 Apr

Fingerprint

Replicon
Ribavirin
Hepacivirus
Interferons
Luciferases
Genotype
Therapeutics
Mutation
Neomycin
Chronic Hepatitis C
Viral Load
Reporter Genes
Transfection
Viruses
Genes
Proteins

Keywords

  • Hepatitis C virus
  • Interferon and ribavirin combination therapy
  • NS5B polymorphism
  • Replicon
  • Viral proliferation

ASJC Scopus subject areas

  • Virology

Cite this

Possible molecular mechanism of the relationship between NS5B polymorphisms and early clearance of hepatitis C virus during interferon plus ribavirin treatment. / Nakamura, Mitsuyasu; Saito, Hidetsugu; Ikeda, Masanori; Tada, Shinichiro; Kumagai, Naoki; Kato, Nobuyuki; Shimotohno, Kunitada; Hibi, Toshifumi.

In: Journal of Medical Virology, Vol. 80, No. 4, 04.2008, p. 632-639.

Research output: Contribution to journalArticle

Nakamura, Mitsuyasu ; Saito, Hidetsugu ; Ikeda, Masanori ; Tada, Shinichiro ; Kumagai, Naoki ; Kato, Nobuyuki ; Shimotohno, Kunitada ; Hibi, Toshifumi. / Possible molecular mechanism of the relationship between NS5B polymorphisms and early clearance of hepatitis C virus during interferon plus ribavirin treatment. In: Journal of Medical Virology. 2008 ; Vol. 80, No. 4. pp. 632-639.
@article{115ad56c9df94bc0b72a506ed7ee022d,
title = "Possible molecular mechanism of the relationship between NS5B polymorphisms and early clearance of hepatitis C virus during interferon plus ribavirin treatment",
abstract = "We previously reported the relationship between viral polymerase polymorphisms and the initial decline in viral load induced by interferon-α and ribavirin therapy in genotype 1b-related chronic hepatitis C patients. The presence of E124K and I85V of NS5B was closely associated with viral clearance at 8 weeks of treatment. The aim of this study was to investigate the mechanisms by which this polymorphism of NS5B protein affects early viral clearance. We used a replicon system derived from strain O, genotype 1b virus. Three mutants (V85I), (K124E), and (V85I/K124E) were introduced to the replicon. OR6c, a derivative of HuH7 cells, was transfected with the replicon including a luciferase reporter gene. Luciferase activities were measured 72 hr post-transfection. All three mutants showed higher luciferase activity than that of the wild type, and the V85I mutant showed the highest activity. This result was also confirmed by neomycin gene-containing replicons with same mutations. All replicons were down-regulated by ribavirin, but the level of reduction in the V85I mutant was the lowest. Our results suggested that this mutation at least partly contributes to resistance to early viral clearance during interferon and ribavirin combination therapy.",
keywords = "Hepatitis C virus, Interferon and ribavirin combination therapy, NS5B polymorphism, Replicon, Viral proliferation",
author = "Mitsuyasu Nakamura and Hidetsugu Saito and Masanori Ikeda and Shinichiro Tada and Naoki Kumagai and Nobuyuki Kato and Kunitada Shimotohno and Toshifumi Hibi",
year = "2008",
month = "4",
doi = "10.1002/jmv.21125",
language = "English",
volume = "80",
pages = "632--639",
journal = "Journal of Medical Virology",
issn = "0146-6615",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - Possible molecular mechanism of the relationship between NS5B polymorphisms and early clearance of hepatitis C virus during interferon plus ribavirin treatment

AU - Nakamura, Mitsuyasu

AU - Saito, Hidetsugu

AU - Ikeda, Masanori

AU - Tada, Shinichiro

AU - Kumagai, Naoki

AU - Kato, Nobuyuki

AU - Shimotohno, Kunitada

AU - Hibi, Toshifumi

PY - 2008/4

Y1 - 2008/4

N2 - We previously reported the relationship between viral polymerase polymorphisms and the initial decline in viral load induced by interferon-α and ribavirin therapy in genotype 1b-related chronic hepatitis C patients. The presence of E124K and I85V of NS5B was closely associated with viral clearance at 8 weeks of treatment. The aim of this study was to investigate the mechanisms by which this polymorphism of NS5B protein affects early viral clearance. We used a replicon system derived from strain O, genotype 1b virus. Three mutants (V85I), (K124E), and (V85I/K124E) were introduced to the replicon. OR6c, a derivative of HuH7 cells, was transfected with the replicon including a luciferase reporter gene. Luciferase activities were measured 72 hr post-transfection. All three mutants showed higher luciferase activity than that of the wild type, and the V85I mutant showed the highest activity. This result was also confirmed by neomycin gene-containing replicons with same mutations. All replicons were down-regulated by ribavirin, but the level of reduction in the V85I mutant was the lowest. Our results suggested that this mutation at least partly contributes to resistance to early viral clearance during interferon and ribavirin combination therapy.

AB - We previously reported the relationship between viral polymerase polymorphisms and the initial decline in viral load induced by interferon-α and ribavirin therapy in genotype 1b-related chronic hepatitis C patients. The presence of E124K and I85V of NS5B was closely associated with viral clearance at 8 weeks of treatment. The aim of this study was to investigate the mechanisms by which this polymorphism of NS5B protein affects early viral clearance. We used a replicon system derived from strain O, genotype 1b virus. Three mutants (V85I), (K124E), and (V85I/K124E) were introduced to the replicon. OR6c, a derivative of HuH7 cells, was transfected with the replicon including a luciferase reporter gene. Luciferase activities were measured 72 hr post-transfection. All three mutants showed higher luciferase activity than that of the wild type, and the V85I mutant showed the highest activity. This result was also confirmed by neomycin gene-containing replicons with same mutations. All replicons were down-regulated by ribavirin, but the level of reduction in the V85I mutant was the lowest. Our results suggested that this mutation at least partly contributes to resistance to early viral clearance during interferon and ribavirin combination therapy.

KW - Hepatitis C virus

KW - Interferon and ribavirin combination therapy

KW - NS5B polymorphism

KW - Replicon

KW - Viral proliferation

UR - http://www.scopus.com/inward/record.url?scp=40549128699&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40549128699&partnerID=8YFLogxK

U2 - 10.1002/jmv.21125

DO - 10.1002/jmv.21125

M3 - Article

C2 - 18297719

AN - SCOPUS:40549128699

VL - 80

SP - 632

EP - 639

JO - Journal of Medical Virology

JF - Journal of Medical Virology

SN - 0146-6615

IS - 4

ER -