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C型肝炎ウイルスの増殖適応変異と病原性の研究

Research Project

Project/Area Number 19041047
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKobe University

Principal Investigator

堀田 博  Kobe University, 大学院・医学研究科, 教授 (40116249)

Co-Investigator(Kenkyū-buntansha) 勝二 郁夫  神戸大学, 大学院・医学研究科, 准教授 (40356241)
足達 哲也  神戸大学, 医学部, 助教 (60345014)
定 清直  福井大学, 医学部, 教授 (10273765)
長野 基子  神戸大学, 大学院・医学系研究科, 助教 (90304089)
Project Period (FY) 2007 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥7,900,000 (Direct Cost: ¥7,900,000)
Fiscal Year 2008: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2007: ¥3,900,000 (Direct Cost: ¥3,900,000)
Keywordsウイルス / 遺伝子 / 感染症
Research Abstract

HCV J6/JFH-1株をHuh-7.5細胞で27、38、47代継代したウイルス株(P-27、P-38、P-47)は、親株に比べて50〜300倍高い感染性ウイルス粒子産生能を示した。P-27には8ヵ所(E2に4ヵ所、NS2に2ヵ所、NS5AとNS5Bに1ヵ所ずつ)のアミノ酸変異がみられ、P-38では上記8ヵ所に加えてCoreに1ヵ所、P-47では更に5'-UTRとNS5Bに1ヵ所ずつの変異がみられた。reverse genetics法により親株にP-27で見られた8ヵ所の変異をすべて導入すると感染性ウイルス粒子産生能が約10倍増加することを確認した。しかし、7ヵ所以下の部分的変異導入では感染性ウイルス粒子産生能の有意な増加は観察されなかった。P-27は親株に比べて抗CD81抗体による吸着阻害を受けにくく、その性質はE2の単一変異(N534H)によるものであった。この変異によるE2の糖鎖付加の欠失が、ウイルスレセプターとの相互作用に影響を及ぼして、HCVの感染効率を増加させている可能性が考えられた。さらに、P-27ではウイルス遺伝子複製能とウイルスタンパク質合成能が親株に比べて軽度増加していた。このような複数の変異が複合的に作用して顕著な感染性ウイルス粒子産生能の増加をもたらしたものと考えられた。
また、HCV感染細胞と非感染細胞を用いてプロテオーム解析を行い、感染の持続に伴って発現が減少する宿主タンパク質として、FABP1を同定した。FABP1は脂肪酸取込みに重要な役割を果たしているが、HCV感染によるFABP1発現の低下が、細胞の脂質代謝等にどのように影響を及ぼしているかについて、現在解析を進めている。同様に、肝細胞への糖取込みに重要な役割を果たしているGLUT2の発現がHCV複製により抑制されることも明らかにした。mRNA定量やルシフェラーゼレポーターを用いたプロモーターアッセイにより、GLUT2発現の抑制が転写レベルでおこっていること、及び肝細胞において重要な転写因子HNF1αが関与することを明らかにした。HCVが肝細胞の糖・脂質代謝異常を引き起こす分子機序を考える上で興味ある知見である。

Report

(2 results)
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (30 results)

All 2009 2008 2007 Other

All Journal Article (14 results) (of which Peer Reviewed: 14 results) Presentation (12 results) Remarks (4 results)

  • [Journal Article] Efficient production of infectious hepatitis C virus with adaptive mutations in cultured hepatoma2009

    • Author(s)
      Bungyoku Yasuaki
    • Journal Title

      J Gen Virol (In press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] HCV replication suppresses cellular glucose uptake through down-regulation of cell surface expression of glucose transporters2009

    • Author(s)
      Kasai Daisuke
    • Journal Title

      J Hepatol (In press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pegylated interferon plus ribavirin combination therapy for chronic hepatitis C with high viral load of serum hepatitis C virus RNA, genotype 1b, discontinued on attaining sustained virological response at week 16 after onset of acute pancreatitis2009

    • Author(s)
      Kim Soo Ryang
    • Journal Title

      Digestion 79(1)

      Pages: 36-39

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hepatitis C virus infection induces apoptosis through a Bax-triggered, mitochondria-mediated, caspase-3-dependent pathway2008

    • Author(s)
      Deng Lin
    • Journal Title

      J Virol 82(21)

      Pages: 10375-10385

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hepatitis C virus NS5A protein interacts with and negatively regulates the non-receptor protein-tyrosine kinase Syk2008

    • Author(s)
      Inubushi Sachiko
    • Journal Title

      J Gen Virol 89(5)

      Pages: 1231-1242

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sequence variation in the hepatitis C virus NS5A protein predicts clinical outcome of pegylated interferon/ribavirin combination therapy2008

    • Author(s)
      EI-Shamy Ahmed
    • Journal Title

      Hepatology 48

      Pages: 138-47

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Usefulness of new immuno-radiometric assay of HCV core antigen to predict virological response during PEG-IFN/RBV combination therapy for chronic hepatitis with high viral loads of serum HCV RNA genotype 1b2008

    • Author(s)
      Sasase Noriko
    • Journal Title

      Intervirology 51 Suppl 1

      Pages: 70-75

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel subgenotypes of hepatitis B virus genotypes C and D in Papua, Indonesia2008

    • Author(s)
      Lusida Maria Inge
    • Journal Title

      J Clin Microbiol 46(7)

      Pages: 12160-2166

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hepatitis C virus NS5A protein interacts with and negatively regulates the non-receptor protein-tyrosine kinase Syk2008

    • Author(s)
      Inubushi Sachiko
    • Journal Title

      J Gen Virol (In press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Risk of hepatocellular carcinoma and secondary structure of hepatitis C virus (HCV)NS3 protein amino-terminus among patients infected with HCV subtype lb.2007

    • Author(s)
      Nishise Yuko
    • Journal Title

      J Infect Dis 196(7)

      Pages: 1006-1009

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prediction of efficient virological response to pegylated interferon /ribavirin combination therapy by NS5A sequences of hepatitis C viras and anti-NS5A antibodies in oretreatment sera.2007

    • Author(s)
      El-Shamy Ahmed
    • Journal Title

      Microbiol Immunol 51(4)

      Pages: 471-482

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Complete genomes for hepatitis C virus subtypes 6f, 6i, 6j and 6m:viral genetic diversity among Thai blood donors and infected spouses.2007

    • Author(s)
      Lu Ling
    • Journal Title

      J Gen Virol 88(5)

      Pages: 1505-1518

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Is hepatitis C virus NS3 protease quasispecies heterogeneity redictive of progression from cirrhosis to hepatocellular carcinoma?2007

    • Author(s)
      Vallet Sophie
    • Journal Title

      J Viral Hepat 14(2)

      Pages: 96-106

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel regulation of MHC class II function in B cells.2007

    • Author(s)
      Matsuki Yohei
    • Journal Title

      EMBO J 26(3)

      Pages: 846-854

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Presentation] Sequence variation of the hepatitis C virus genome and its correlation with viral pathogenicity2009

    • Author(s)
      Hotta Hak
    • Organizer
      8th Asia Pacific Congress of Medical Virology
    • Place of Presentation
      香港(中国)
    • Related Report
      2008 Annual Research Report
  • [Presentation] Down-regulation of glucose transporter expression and glucose uptake by hepatitisc virus replication2009

    • Author(s)
      Adachi Tetuya
    • Organizer
      8th Asia Pacific Congress of Medical Virology
    • Place of Presentation
      香港(中国)
    • Related Report
      2008 Annual Research Report
  • [Presentation] C型肝炎ウイルス感染はミトコンドリア障害を介するアポトーシスを誘導する2008

    • Author(s)
      Deng Lin
    • Organizer
      第61回日本細菌学会関西支部総会
    • Place of Presentation
      京都
    • Year and Date
      2008-11-08
    • Related Report
      2008 Annual Research Report
  • [Presentation] Recent advances in the pathogenesis and treatment of hepatitis C viru infections2008

    • Author(s)
      Hotta Hak
    • Organizer
      Joint Meeting of International Society of Chemotherapy for Infection and Cancer and Western Pacific Society of Chemotherapy
    • Place of Presentation
      杭州(中国)
    • Year and Date
      2008-09-13
    • Related Report
      2008 Annual Research Report
  • [Presentation] HCV induces nucleolar enlargement of the host cell that is associated with anti-apoptotic status and cell cycle progression during the chronic persistent phase of infection2008

    • Author(s)
      Hotta Hak
    • Organizer
      15th International symposium on hepatitis C virus & related viruses
    • Place of Presentation
      San Antonio (USA)
    • Related Report
      2008 Annual Research Report
  • [Presentation] HCV infection induces Bax-triggered, mitochondria- mediated, caspase-3-dependent apoptosis. 15th International symposium on hepatitis C virus & related viruses2008

    • Author(s)
      Deng Lin
    • Organizer
      15th International symposium on hepatitis C virus & related viruses
    • Place of Presentation
      San Antonio (USA)
    • Related Report
      2008 Annual Research Report
  • [Presentation] Polymorphism of HCV-1b core protein and interferon/ribavirin resistance-determining region (IRRDR) of NS5A predicts clinical outcome of pegy lated interferon/rivavirin combination therapy2008

    • Author(s)
      Ahmed El-Shamy
    • Organizer
      15th International symposium on hepatitis C virus & related viruses
    • Place of Presentation
      San Antonio (USA)
    • Related Report
      2008 Annual Research Report
  • [Presentation] グルコーストランスポーターGLUT2の発現と肝臓グルコース取り込みにおけるC型肝炎ウイルスの影響に関する検討2008

    • Author(s)
      足達哲也
    • Organizer
      第51回日本糖尿病学会年次学術集会
    • Place of Presentation
      東京
    • Related Report
      2008 Annual Research Report
  • [Presentation] C型肝炎ウイルス感染によるアポトーシスの分子機序の解析2008

    • Author(s)
      Deng Lin
    • Organizer
      第56回日本ウイルス学会学術集会
    • Place of Presentation
      岡山
    • Related Report
      2008 Annual Research Report
  • [Presentation] C型肝炎ウイルスの持続感染は宿主細胞の核小体肥大、アポトーシス感受性低下及び細胞周期進行を誘導する2008

    • Author(s)
      北山喜久美
    • Organizer
      第56回日本ウイルス学会学術集会
    • Place of Presentation
      岡山
    • Related Report
      2008 Annual Research Report
  • [Presentation] Hepatitis C virus infection induces apoptosis via a mitochondrial-related caspase pathway.2007

    • Author(s)
      Deng Ling
    • Organizer
      14th International Meeting on Hepatitis C Virus and Related Viruses
    • Place of Presentation
      Glasgow
    • Year and Date
      2007-09-13
    • Related Report
      2007 Annual Research Report
  • [Presentation] Analysis of adaptive mutants of the J6/JFH-1 strain of hepatitis C virus genotype 2a.2007

    • Author(s)
      Bungyoku Yasuaki
    • Organizer
      14th International Meeting on hepatitis C Virus and Related Viruses
    • Place of Presentation
      Glasgow
    • Year and Date
      2007-09-10
    • Related Report
      2007 Annual Research Report
  • [Remarks]

    • URL

      http://kansen-matrix.jp/

    • Related Report
      2008 Annual Research Report
  • [Remarks]

    • URL

      http://www.med.kobe-u.ac.jp/micro/index.htm

    • Related Report
      2008 Annual Research Report
  • [Remarks]

    • URL

      http://kansen-matrix.jp/

    • Related Report
      2007 Annual Research Report
  • [Remarks]

    • URL

      http://www.med.kobe-u.ac.jp/micro/index.htm

    • Related Report
      2007 Annual Research Report

URL: 

Published: 2007-04-01   Modified: 2018-03-28  

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