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Molecular Mechanisms of Hepatitis B virus cccDNA Formation

Research Project

Project/Area Number 17K09412
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionNational Institute of Infectious Diseases (2019)
Kanazawa University (2017-2018)

Principal Investigator

Kitamura Kouichi  国立感染症研究所, ウイルス第二部, 主任研究官 (70378892)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsB型肝炎ウイルス / ウィルス
Outline of Final Research Achievements

Hepatitis B virus (HBV) infection remains a worldwide health problem that affects more than 350 million people. HBV is one of the major etiological pathogens for liver cirrhosis and hepatocellular carcinoma. HBV covalently closed circular DNA (cccDNA) is a key viral intermediate for persistent infection. However, the molecular mechanism of cccDNA formation has not been clarified. In this project, we found that the host factor flap-endonuclease 1 (FEN1) is pivotal in cccDNA formation. We developed a novel cccDNA formation assay using purified viral precursor DNA with recombinant FEN1, DNA polymerase, and DNA ligase. This study provides new insights into the molecular mechanisms of cccDNA formation and proposes FEN1 as a potential anti-HBV drug target.

Academic Significance and Societal Importance of the Research Achievements

B型肝炎はワクチンの普及により新規感染者数が大幅に減少しているが、一旦感染が成立してしまうと既存の逆転写阻害による抗ウイルス薬は原理的にcccDNAを除去できないため、持続感染者の根治は依然として困難である。また、HBV持続感染患者を想定するような培養下での長期HBV感染細胞において、cccDNAの制御に影響する因子についてはほとんど知見がない。本研究によってcccDNA形成に関わるFEN1というタンパク質の存在が初めて明らかとなり、今後FEN1や関連する宿主因子の分子機構の解明や、これを標的とする抗ウイルス薬開発につながることが期待できる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (17 results)

All 2019 2018 2017 Other

All Journal Article (6 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 6 results,  Open Access: 4 results) Presentation (9 results) (of which Int'l Joint Research: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Different antiviral activities of natural APOBEC3C, APOBEC3G, and APOBEC3H variants against hepatitis B virus2019

    • Author(s)
      Kanagaraj Arun、Sakamoto Naoya、Que Lusheng、Li Yingfang、Mohiuddin Md、Koura Miki、Wakae Kousho、Kurachi Makoto、Muramatsu Masamichi、Kitamura Kouichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 518 Issue: 1 Pages: 26-31

    • DOI

      10.1016/j.bbrc.2019.08.003

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Expression of estrogen receptor alpha is associated with pathogenesis and prognosis of human papillomavirus‐positive oropharyngeal cancer2019

    • Author(s)
      Kano Makoto、Kondo Satoru、Wakisaka Naohiro、Wakae Kosho、Aga Mituharu、Moriyama‐Kita Makiko、Ishikawa Kazuya、Ueno Takayoshi、Nakanishi Yosuke、Hatano Miyako、Endo Kazuhira、Sugimoto Hisashi、Kitamura Kouichi、Muramatsu Masamichi、Yoshizaki Tomokazu
    • Journal Title

      International Journal of Cancer

      Volume: 145 Issue: 6 Pages: 1547-1557

    • DOI

      10.1002/ijc.32500

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Keratinocyte differentiation induces APOBEC3A, 3B, and mitochondrial DNA hypermutation2018

    • Author(s)
      Wakae Kousho、Nishiyama Tomoaki、Kondo Satoru、Izuka Takashi、Que Lusheng、Chen Cong、Kase Kina、Kitamura Kouichi、Mohiuddin Md、Wang Zhe、Ahasan Md Monjurul、Nakamura Mitsuhiro、Fujiwara Hiroshi、Yoshizaki Tomokazu、Hosomochi Kazuyoshi、Tajima Atsushi、Nakahara Tomomi、Kiyono Tohru、Muramatsu Masamichi
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 9745-9745

    • DOI

      10.1038/s41598-018-27930-z

    • NAID

      120006602143

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Flap endonuclease 1 is involved in cccDNA formation in the hepatitis B virus2018

    • Author(s)
      Kitamura Kouichi、Que Lusheng、Shimadu Miyuki、Koura Miki、Ishihara Yuuki、Wakae Kousho、Nakamura Takashi、Watashi Koichi、Wakita Takaji、Muramatsu Masamichi
    • Journal Title

      PLOS Pathogens

      Volume: 14 Issue: 6 Pages: e1007124-e1007124

    • DOI

      10.1371/journal.ppat.1007124

    • NAID

      120006602144

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression and subcellular localisation of AID and APOBEC3 in adenoid and palatine tonsils2018

    • Author(s)
      Seishima Noriko、Kondo Satoru、Wakae Kousho、Wakisaka Naohiro、Kobayashi Eiji、Kano Makoto、Moriyama-Kita Makiko、Nakanishi Yosuke、Endo Kazuhira、Imoto Tomoko、Ishikawa Kazuya、Sugimoto Hisashi、Hatano Miyako、Ueno Takayoshi、Koura Miki、Kitamura Koichi、Muramatsu Masamichi、Yoshizaki Tomokazu
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 918-918

    • DOI

      10.1038/s41598-017-18732-w

    • NAID

      120006602142

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular characterization of AID-mediated reduction of hepatitis B virus transcripts2017

    • Author(s)
      Que Lusheng、Liu Guangyan、Kitamura Kouichi、Wakae Kousho、Li Yingfang、Nishitsuji Hironori、Ujino Saneyuki、Shimotohno Kunitada、Muramatsu Masamichi
    • Journal Title

      Virology

      Volume: 510 Pages: 281-288

    • DOI

      10.1016/j.virol.2017.07.035

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Difference of hepatitis B virus restriction activity between natural variants in APOBEC3C, 3G, and 3H2019

    • Author(s)
      Kouichi Kitamura, Arun Kanagaraj, Naoya Sakamoto, Lusheng Que, Mohiuddin Md, Miki Koura, Kousho Wakae, Masamichi Muramatsu
    • Organizer
      7th Japan-Taiwan-Korea HBV Research Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] B型肝炎ウイルスcccDNAの形成に関与するDNA修復因子FEN12019

    • Author(s)
      喜多村晃一、Lusheng Que、島津美幸, 小浦美樹、村松正道
    • Organizer
      日本生化学会北陸支部第37回大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] B型肝炎ウイルスcccDNA形成過程におけるFEN1の役割の検討2018

    • Author(s)
      村松正道, 喜多村晃一
    • Organizer
      第54回日本肝臓学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] B型肝炎ウイルスcccDNA形成に関与するDNA修復因子の解析2018

    • Author(s)
      喜多村晃一, 小浦美樹, 村松正道
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Presentation] B型肝炎ウイルスcccDNAの形成・維持に関わる宿主因子の解析2017

    • Author(s)
      喜多村晃一
    • Organizer
      第14回ウイルス学キャンプin湯河原
    • Related Report
      2017 Research-status Report
  • [Presentation] B型肝炎ウイルスcccDNAに作用する宿主因子2017

    • Author(s)
      喜多村晃一
    • Organizer
      平成29年度 北陸腸内細菌研究会
    • Related Report
      2017 Research-status Report
  • [Presentation] HBV cccDNA形成に作用する因子のin vitro解析2017

    • Author(s)
      喜多村晃一、島津美幸、小浦美樹、村松正道
    • Organizer
      第65回日本ウイルス学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] TGF-β-mediated suppression of HBV RNA through AID-dependent recruitment of an RNA exosome complex2017

    • Author(s)
      喜多村晃一、島津美幸、小浦美樹、村松正道
    • Organizer
      国際サイトカイン・インターフェロン学会 ICIS2017 in Kanazawa
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] B型肝炎ウイルスcccDNA形成過程に関与するflapエンドヌクレアーゼFEN1の解析2017

    • Author(s)
      喜多村晃一、島津美幸、小浦美樹、村松正道
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Remarks] B型肝炎ウイルス複製の鋳型となるDNAの形成に関わる酵素を発見

    • URL

      https://www.kanazawa-u.ac.jp/rd/57781

    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] B型肝炎ウイルス(HBV)増殖阻害剤のスクリーニング方法2017

    • Inventor(s)
      村松正道、喜多村晃一
    • Industrial Property Rights Holder
      国立大学法人金沢大学
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2017-152717
    • Filing Date
      2017
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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