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Analyzing the contribution of intracellular localization of hepatitis C virus replication complex for the drug resistance.

Research Project

Project/Area Number 17590627
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionUniversity of Yamanashi

Principal Investigator

MAEKAWA Shinya  University of Yamanashi, Graduate School of Medicine and Engineering, Assistant Professor, 大学院医学工学総合研究部, 講師 (70397298)

Co-Investigator(Kenkyū-buntansha) ENOMOTO Nobuyuki  University of Yamanashi, Graduate School of Medicine and Engineering, Professor, 大学院医学工学総合研究部, 教授 (20251530)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsHepatitis C Virus / NS5A protein / HCV replicon / interferon / インターフェロン耐性 / C型肝炎ウイルス / レプリコン / 複製複合体 / コレステロール / スフィンゴ脂質 / 脂質ラフト
Research Abstract

This research is aimed to disclose the relationship between intracellular localization of hepatitis C virus (HCV) replication complex and the effect of anti-viral drugs such as interferon-alpha, and finally to develop new anti-HCV strategies through understanding of viral replication mechanism(s) in the replication complex.
Recently, micro-domains of organelle membranes rich in sphingomyelin and cholesterol in the form of "lipid rafts" have been considered to act as a scaffold for HCV replication complex formation, indicating the possibility that the lipid raft could be a new therapeutic target. In the present study, we investigated the effect of myriocin, an inhibitor of sphingomyelin synthesis, on HCV replication using an HCV-subgenomic replicon system, as well as the infectious HCV culture system. We also investigated the combined effect of myriocin plus interferon-alpha, or myriocin plus simvastatin, on HCV replication. Myriocin suppressed intracellular RNA replication of both genotype lb subgenomic HCV replicon RNA and genotype 2a infectious HCV RNA in a time-and dose-dependent manner (subgenomic HCV-lb, max. 70% at 120 hours ; genomic HCV-2a, max. 60% at 96 hours). Combination treatment with myriocin plus IFN or simvastatin attenuated intracellular HCV-RNA replication synergistically.
Our data demonstrate that both the sphingomyelin synthesis inhibitor and HMG-CoA inhibitor strongly suppress HCV replication, irrespective of genotype, indicating that the lipid metabolism of the host could be a novel target for HCV therapy.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (12 results)

All 2006

All Journal Article (12 results)

  • [Journal Article] Negative regulation of intracellular hepatitis C virus replication by interferon regulatory factor 3.2006

    • Author(s)
      Yamashiro T, Maekawa S, Enomoto N. et al.
    • Journal Title

      Journal of Gastroenterology Aug; 41(8)

      Pages: 750-757

    • NAID

      10018255879

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expressionnal screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication2006

    • Author(s)
      Itsui Y, Maekawa S, Enomoto N, et al.
    • Journal Title

      Journal of Viral Hepatitis Oct;13(10)

      Pages: 690-700

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Site-specific nutation of the interferon sensitivity-determining region (ISDR) modulates hepatitis C virus replication.2006

    • Author(s)
      Kohashi T, Maekawa S, Enomoto N, et al.
    • Journal Title

      Journal of Viral Hepatitis Sep;13(9)

      Pages: 582-590

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Divergent activities of interferon-alpha subtypes against intracellular hepatitis C virus replication2006

    • Author(s)
      Koyama T, Maekawa S, Enomoto N, et al.
    • Journal Title

      Hepatology Research Jan;34(1)

      Pages: 41-49

    • NAID

      10020406147

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Negative regulation of intracellular hepatitis C virus replication by interferon regulatory factor 3.2006

    • Author(s)
      Yamashiro T, Sakamoto N, Kurosaki M, Kanazawa N, Tanabe Y, Nakagawa M, Chen CH, Itsui Y, Koyama T, Takeda Y, Maekawa S, Enomoto N, Sakugawa H, Watanabe M.
    • Journal Title

      J Gastroenterol. 41(8)

      Pages: 750-7

    • NAID

      10018255879

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication.2006

    • Author(s)
      Itsui Y, Sakamoto N, Kurosaki M, Kanazawa N, Tanabe Y, Koyama T, Takeda Y, Nakagawa M, Kakinuma S, Sekine Y, Maekawa S, Enomoto N, Watanabe M.
    • Journal Title

      J Viral Hepat. 13(10)

      Pages: 690-700

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Site-specific mutation of the interferon sensitivity-determining region (ISDR) modulates hepatitis C virus replication.2006

    • Author(s)
      Kohashi T, Maekawa S, Sakamoto N, Kurosaki M, Watanabe H, Tanabe Y, Chen CH, Kanazawa N, Nakagawa M, Kakinuma S, Yamashiro T, Itsui Y, Koyama T, Enomoto N, Watanabe M.
    • Journal Title

      J Viral Hepat. 13(9)

      Pages: 582-90

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Divergent activities of interferon-alpha subtypes against intracellular hepatitis C virus replication2006

    • Author(s)
      Koyama T, Sakamoto N, Tanabe Y, Nakagawa M, Itsui Y, Takeda Y, Kakinuma S, Sekine Y, Maekawa S, Yanai Y, Kurimoto M, Watanabe M.
    • Journal Title

      Hepatol Res. 34(1)

      Pages: 41-9

    • NAID

      10020406147

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Negative regulation of intracellular hepatitis C virus replication by interferon regulatory factor 3.2006

    • Author(s)
      Yamashiro T, Maekawa S, Enomoto N, et al.
    • Journal Title

      Journal of Gastroenterology Aug;41(8)

      Pages: 750-757

    • NAID

      10018255879

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication.2006

    • Author(s)
      Itsui Y, Maekawa S, Enomoto N, et al.
    • Journal Title

      Journal of Viral Hepatitis Oct;13(10)

      Pages: 690-700

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Site-specific mutation of the interferon sensitivity-determining region (ISDR) modulates hepatitis C virus replication.2006

    • Author(s)
      Maekawa S, Kohashi T, Enomoto N, et al.
    • Journal Title

      Journal of Viral Hepatitis Sep;13(9)

      Pages: 582-590

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Divergent activities of interferon-alpha subtypes against intracellular hepatitis C virus replication.2006

    • Author(s)
      Koyama T, Maekawa S, Enomoto N, et al.
    • Journal Title

      Hepatology Research Jan;34(1)

      Pages: 41-49

    • NAID

      10020406147

    • Related Report
      2006 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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