Systems Virology for understanding viral pathogenesis

• Project/Area Number: 16KT0111
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Complex Systems Disease Theory
• Research Institution: Kyoto University
• Principal Investigator: Noda Takeshi 京都大学, ウイルス・再生医科学研究所, 教授 (00422410)
• Co-Investigator(Kenkyū-buntansha): 佐藤 佳 東京大学, 医科学研究所, 准教授 (10593684) ; 渡士 幸一 国立感染症研究所, ウイルス第二部, 主任研究官 (40378948) ; 岩見 真吾 九州大学, 理学研究院, 准教授 (90518119)
• Project Period (FY): 2016-07-19 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2018: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2016: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 数理解析 / エボラウイルス / C型肝炎ウイルス / ヒト免疫不全ウイルス / HIV / ウイルス / ウイルス感染症 / ウイルス学

Outline of Final Research Achievements

By combining experiments and mathematical modeling, we try to understand Ebola virus pathogenesis, human immunodeficient virus replication mechanism, and antiviral effects against Hepatitis B virus quantitatively. We obtained data set including virus titers, the amount of cytokines and chemokines, viral genome sequences, and so on, and analyzed them by mathematics. We found several important host factors involved in Ebola virus pathogenesis and Human immunodeficiency virus replication in vivo. In addition, we found proper combination of three antiviral drugs against Hepatitis B virus that decreases the emergence of the antiviral-resistant virus.

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的意義は、数理科学的な解析を駆使する事で統合的視点からウイルス感染というシステム全体を眺め、病態の発症や薬剤の効果を体系的に理解できる点にある。これらの研究を通じて、実験科学で得られた成績（例：感染個体におけるウイルス増殖機構や重症度など）に新たな意味や価値を付加することができた。いくつかの実験データを基に開発した数理モデルを用いて、最適な組み合わせの抗ウイルス薬を予測し、実際に耐性ウイルスの出現頻度が少ない薬剤の組み合わせを見出すことにも成功した。

Research Products

• [Journal Article] Epidermal growth factor receptor is a host entry cofactor triggering hepatitis B virus internalization (2019)
  • Author(s): M. Iwamoto, W. Saso, R. Sugiyama, K. Ishii, M. Ohki, S. Nagamori, R. Suzuki, H. Aizaki, A. Ryo, J-H Yun, S-Y Park, N. Ohtani, M. Muramatsu, S. Iwami, Y. Tanaka, C. Sureau, T. Wakita and K. Watashi
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 116 Issue: 17 Pages: 8487-8492
  • DOI: 10.1073/pnas.1811064116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Defect in Influenza A Virus Particle Assembly Specific to Primary Human Macrophages. (2018)
  • Author(s): Bedi S, Noda T, Kawaoka Y, Ono A.
  • Journal Title: MBio Volume: 9 Issue: 5
  • DOI: 10.1128/mbio.01916-18
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cryo-EM structure of the Ebola virus nucleoprotein-RNA complex at 3.6 A resolution. (2018)
  • Author(s): Sugita Y, Matsunami H, Kawaoka Y, Noda T, Wolf M.
  • Journal Title: Nature Volume: 563 Issue: 7729 Pages: 137-140
  • DOI: 10.1038/s41586-018-0630-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. (2018)
  • Author(s): Mahgoub M, Yasunaga JI, Iwami S, Nakaoka S, Koizumi Y, Shimura K, Matsuoka M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 115 Issue: 6 Pages: 529-538
  • DOI: 10.1073/pnas.1715724115
  • NAID: 120006697286
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human-specific adaptations in Vpu conferring anti-tetherin activity are critical for efficient early HIV-1 replication in vivo. (2017)
  • Author(s): Eri Yamada, Shinji Nakaoka, Lukas Klein, Elisabeth Reith, Simon Langer, Kristina Hopfensperger, Shingo Iwami, Gideon Schreiber, Frank Kirchhoff, Yoshio Koyanagi, Daniel Sauter & Kei Sato
  • Journal Title: Cell Host & Microbe Volume: 23 Issue: 1 Pages: 110-120
  • DOI: 10.1016/j.chom.2017.12.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments. (2017)
  • Author(s): Ohashi HK, Koizumi Y, Fukano K, Wakita T, Perelson AS, Iwami S, Watashi K
  • Journal Title: Proc Acad Natl Acad USA Volume: 114 Issue: 23
  • DOI: 10.1073/pnas.1705234114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation. (2017)
  • Author(s): Yusuke Nakano, Naoko Misawa, Guillermo Juarez-Fernandez, Miyu Moriwaki, Shinji Nakaoka, Takaaki Funo, Eri Yamada, Andrew Soper, Rokusuke Yoshikawa, Diako Ebrahimi, Yuuya Tachiki, Shingo Iwami, Reuben S. Harris, Yoshio Koyanagi & Kei Sato
  • Journal Title: PLOS Pathogens Volume: 13 Issue: 5 Pages: 31-31
  • DOI: 10.1371/journal.ppat.1006348
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection (2017)
  • Author(s): Koizumi Y, Ohashi H, Nakajima S, Tanaka Y, Wakita T, Perelson AS, Iwami S, Watashi K
  • Journal Title: Proc Natl Acad Sci U S A Volume: 114(8) Issue: 8 Pages: 1922-1927
  • DOI: 10.1073/pnas.1610197114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Duration of SHIV production by infected cells is not exponentially distributed: Implications for estimates of infection parameters and antiviral efficacy (2017)
  • Author(s): CA. Beauchemin, T. Miura, S. Iwami
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 42765-42765
  • DOI: 10.1038/srep42765
  • NAID: 120005997746
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modelling Ebola virus dynamics: Implications for therapy. (2016)
  • Author(s): Martyushev A, Nakaoka S, Sato K, Noda T, Iwami S.
  • Journal Title: Antiviral Res Volume: 135 Pages: 62-73
  • DOI: 10.1016/j.antiviral.2016.10.004
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Quantifying the effect of Vpu on the promotion of HIV-1 replication in the humanized mouse model (2016)
  • Author(s): Ikeda H, Nakaoka S, de Boer RJ, Morita S, Misawa N, Koyanagi Y, Aihara K, Sato K, Iwami S
  • Journal Title: Retrovirology Volume: 13 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s12977-016-0252-2
  • NAID: 120006353849
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Validating experimentally derived knowledge about influenza A defective interfering particles. (2016)
  • Author(s): Liao LE, Iwami S, Beauchemin CA.
  • Journal Title: J R Soc Interface. Volume: 13 Pages: 124-124
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant