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Hepatitis B virus mutations affecting synthesis of relaxed-circular viral DNA : Relation to disease severity

Research Project

Project/Area Number 18599003
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionOsaka University

Principal Investigator

OHKAWA Kazuyoshi  Osaka University, Graduate School of Medicine, Assistant professor (80432540)

Co-Investigator(Kenkyū-buntansha) TAKEHARA Tetsuo  Osaka University, Graduate School of Medicine, Associate professor (70335355)
HIRAMATSU Naoki  Osaka University, Graduate School of Medicine, Assistant professor (30362700)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,730,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
KeywordsHepatitis B virus (HBV) / HBV mutation / Relaxed-circular (RC) HBV DNA
Research Abstract

There are three kinds of viral HBV DNAs, the single-stranded (SS) HBV DNA, the double-stranded linear (DL) HBV DNA and the double-stranded relaxed-circular (RC) HBV DNA, in HBV-infected cells. Among them, only the RC HBV DNA can form the mature HBV virion with infectivity. In this study, we investigated HBV mutations affecting RC HBV DNA synthesis and its involvement in the pathogenesis of HBV-related liver diseases.
1) Identification of the accountable HBV mutation for an increase of RC HBV DNA synthesis in a patient with tvpe B chronic hepatitis showing lethal exacerbation.
We experienced a patient with type B chronic hepatitis showing lethal disease exacerbation. From serum samples at 1 year before exacerbation (P1) and after exacerbation (P2), the full-length HBV DNAs were obtained and designated as HBV P1 and P2 strains. When the HBV P1 and P2 strains were expressed in the cultured cells, the RC HBV DNA level was higher in P2-expressing cells than in P1-expressing ones. Further deta … More iled analyses showed that a G-to-A mutation at nt 2790 from P1 to P2 was an accountable mutation for an increase of RC HBV DNA synthesis and the subsequent disease deterioration in this patient.
2) Relation of HBV mutations affecting the the RC HBV DNA sythesis to the disease severity in type B acute and chronic liver disease.
Thus far, three regions, α (nt2817-2936), γ (nt1909-2141) and δ (nt1373-1589), have been shown to be cis-acting elements which play an important role in RC HBV DNA synthesis. In this study, we carried out sequencing analysis of full-length HBV DNA in 44 patients with type B chronic liver disease and 15 patients with type B acute liver disease. The degree of mutations in the α, γ and δ regions was correlated with the disease severity. In patients with chronic liver disease, the degree of mutations in the α and δ regions was higher in patients with cirrhosis and hepatocellular carcinoma than in those with chronic hepatitis (p=0.006 and p=0.05). As for patients with acute liver disease, patients with fulminant hepatitis had the higher degree of mutations in the α, and γ regions than those with acute self-limited hepatitis (p=0.03 and p=0.01). These results suggest that the high degree of mutations within these regions may affect RC HBV DNA synthesis and viral replicative competence, resulting in the serious liver disease in both acute and chronic HBV infection. Less

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (21 results)

All 2008 2007 2006

All Journal Article (13 results) (of which Peer Reviewed: 6 results) Presentation (8 results)

  • [Journal Article] Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine.2008

    • Author(s)
      Kurashige N, Hiramatsu N, Ohkawa K, et. al.
    • Journal Title

      Hepatology Research 38

      Pages: 450-6

    • NAID

      10024148320

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Early emergence of entecavir-resistant hepatitis B virus in a patient with hepatitis B virus/human immunodeficiency virus coinfection.2008

    • Author(s)
      Kanada A, Takehara T, Ohkawa K, et. al.
    • Journal Title

      Hepatology Research (in press)

    • NAID

      10024149003

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine2008

    • Author(s)
      Kurashige, N, Hiramatsu, N, Ohkawa, K, et. al.
    • Journal Title

      Hepatol Res 38

      Pages: 450-456

    • NAID

      10024148320

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Early emergence of entecavir-resistant hepatitis B virus in a patient with hepatitis B virus/human immunodeficiency virus coinfection2008

    • Author(s)
      Kanada, A, Takehara, T, Ohkawa, K, et. al.
    • Journal Title

      Hepatol Res (in press)

    • NAID

      10024149003

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine.2008

    • Author(s)
      Kurashige N, Hiramatsu N, Ohkawa K, et. al.
    • Journal Title

      Hepatology Research (in press)

    • NAID

      10024148320

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor2007

    • Author(s)
      Tatsumi T, Takehara T, Yamaguchi S, Sasakawa A, Sakamori R, Ohkawa, K, et. al.
    • Journal Title

      Hepatology 45

      Pages: 22-30

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFNalpha gene to mice.2007

    • Author(s)
      Takehara T, Uemura A, Tatsumi T, Suzuki T, Kimura R, Shiotani A, Ohkawa K, et. al.
    • Journal Title

      Int J Cancer 120

      Pages: 1252-60

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Type B fulminant hepatitis is closely associated with a highly mutated hepatitis B virus strain.2007

    • Author(s)
      Kanada A, Takehara T, Ohkawa K, et. al.
    • Journal Title

      Intervirology 50

      Pages: 394-401

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Intrahepatic delivery of a-galatosylceramide pulsed dendritic cells suppresses liver tumor2007

    • Author(s)
      Tatsumi, T, Takehara, T, Yamaguchi, S, Sasakawa, A, Sakamori, R, Ohkawa, K, et. al.
    • Journal Title

      Hepatology 45

      Pages: 22-30

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFN alpha gene to mice2007

    • Author(s)
      Takehara, T, Uemura, A, Tatsumi, T, Suzuki, T, Kimura, R, Shiotani, A, Ohkawa, K, et. al.
    • Journal Title

      Int J Cancer 120

      Pages: 1252-60

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Type B fulminant hepatitis is closely associated with a highly mutated hepatitis B virus strain2007

    • Author(s)
      Kanada, A, Takehara, T, Ohkawa, K, et. al.
    • Journal Title

      Intervirology 50

      Pages: 394-401

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Intrahepatic delivery of alpha-galactosylceramide-pulsed dendritic cells suppresses liver tumor.2007

    • Author(s)
      Tatsumi T, Takehara T, Yamaguchi S, Sasakawa A, Sakamori R, Ohkawa K, et al.
    • Journal Title

      Hepatology 45 (1)

      Pages: 22-30

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Natural killer cell-mediated ablation of metastatic liver tumors by hydrodynamic injection of IFNalpha gene to mice. Int J Cancer 2007; 120 : 1252-60.2007

    • Author(s)
      Takehara T, Uemura A, Tatsumi T, Suzuki T, Kimura R, Shiotani A, Ohkawa K, et al.
    • Journal Title

      Int J Cancer 120 (6)

      Pages: 1252-1260

    • Related Report
      2006 Annual Research Report
  • [Presentation] ラミブジン耐性B型慢性肝炎に対するアデホビル追加治療におけるウイルス変異の意義2007

    • Author(s)
      大川和良, ら
    • Organizer
      第11回日本肝臓学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2007-10-19
    • Related Report
      2007 Annual Research Report
  • [Presentation] VIRAL MUTATIONS AFFECTING EFFICACY OF ADEFOVIR DPIVOXIL THERAPY ADDED TO ONGOING LAMIVUDINE IN CHRONIC HEPATITIS B2007

    • Author(s)
      大川和良, ら
    • Organizer
      第67回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-04
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] VIRAL MUTATIONS AFFECTING EFFICACY OF ADEFOVIR DIPIVOXIL THERAPY ADDED TO ONGOING LAMIVUDINE IN CHRONIC HEPATITIS B2007

    • Author(s)
      大川和良, ら
    • Organizer
      第67回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-04
    • Related Report
      2007 Annual Research Report
  • [Presentation] ラミブジン耐性B型慢性肝疾患に対するアデホビル追加治療における治療効果を規定するウイルス変異の検討2007

    • Author(s)
      大川和良, ら
    • Organizer
      第43回日本肝臓学会総会
    • Place of Presentation
      東京
    • Year and Date
      2007-06-01
    • Related Report
      2007 Annual Research Report
  • [Presentation] B型急性肝炎と劇症肝炎におけるB型肝炎ウイルスDNA全塩基配列の比較2007

    • Author(s)
      金田愛衣美、竹原徹郎、大川和良, ら
    • Organizer
      第93回日本消化器病学会総会
    • Place of Presentation
      青森
    • Year and Date
      2007-04-19
    • Related Report
      2007 Annual Research Report
  • [Presentation] Viral mutations affecting efficacy of adefovir dipivoxil therapy added to ongoing lamivudine in chronic hepatitis B2007

    • Author(s)
      Ohkawa, K, et. al.
    • Organizer
      The 67th annual meeting of Japanese Cancer Association
    • Place of Presentation
      Yokohama, Japan
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine.2006

    • Author(s)
      Kurashige N, Hiramatsu N, Ohkawa K, et. al.
    • Organizer
      57th meeting of the American Association of the Study of Liver Diseases.
    • Place of Presentation
      Boston
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in hepatitis B patients treated with lamivudine2006

    • Author(s)
      Kurashige, N, Hiramatsu, N, Ohkawa, K, et. al.
    • Organizer
      The 57th annual meeting of the American Association of the Study of Liver Diseases
    • Place of Presentation
      Boston, USA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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