Theory for effective antiviral strategy based on multiscale mathematical modeling

• Project/Area Number: 15KT0107
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 特設分野
• Research Field: Mathematical Sciences in Search of New Cooperation
• Research Institution: Kyushu University
• Principal Investigator: Iwami Shingo 九州大学, 理学研究院, 准教授 (90518119)
• Co-Investigator(Kenkyū-buntansha): 中岡 慎治 東京大学, 生産技術研究所, 派遣研究員 (30512040)
• Research Collaborator: NAKAOKA SHINJI
• Project Period (FY): 2015-07-10 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 数理モデル型アプローチ / 定量的データ解析 / マルチスケールモデル / 多階層数理モデル / 偏微分方程式 / データ解析 / 数理モデル / 融合研究 / 構造化個体群モデル / ウイルス感染実験

Outline of Final Research Achievements

In the current era of antiviral drug therapy, combining multiple drugs is a primary approach for improving antiviral effects, reducing the doses of individual drugs, relieving the side effects of strong antiviral drugs, and preventing the emergence of drug-resistant viruses. Mathematical models of viral infection dynamics provide an ideal tool for this purpose. By combining the mathematical modeling of virus dynamics with drug combination theories, we could show the principles by which drug combinations yield a synergistic effect.

Academic Significance and Societal Importance of the Research Achievements

現在、ウイルス感染症やがんなどの治療において、複数の薬剤を組み合わせる「多剤併用治療」が積極的に行われている。これは、治療効果の増幅に加えて、薬剤耐性の出現リスクや副作用、治療費の軽減を目的としている。しかし、これまでの薬剤組み合わせは、実験や治験の成果などを基に、経験的に行われてきた。本研究では、数理モデルを援用する事で、多剤併用治療の最適化を実現する理論を構築し、新しい薬学分野を開拓した。

Research Products

• [Int'l Joint Research] INSERM(フランス)
• [Int'l Joint Research] UNSW(オーストラリア)
• [Int'l Joint Research] ICL(英国)
• [Int'l Joint Research] ロスアラモス国立研究所(米国)
• [Int'l Joint Research] INSERM(フランス)
• [Int'l Joint Research] ライルソン大学(カナダ)
• [Int'l Joint Research] ニューサウスウェールズ大学(オーストラリア)
• [Int'l Joint Research] ライルソン大学(カナダ)
• [Int'l Joint Research] ロスアラモス国立研究所(米国)
• [Int'l Joint Research] ユトレヒト大学(オランダ)
• [Int'l Joint Research] ニューサウスウェールズ大学(オーストラリア)
• [Int'l Joint Research] ハイデルベルグ大学(ドイツ)
• [Int'l Joint Research]
• [Int'l Joint Research] INSERM(France)
• [Int'l Joint Research] Ryerson University(Canada)
• [Int'l Joint Research] Utrecht University(オランダ)
• [Int'l Joint Research] Loa Alamos National Laboratory(米国)
• [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] Mathematical analysis of a transformed ODE from a PDE multiscale model of hepatitis C virus infection (2019)
  • Author(s): Kitagawa K., Kuniya T., Nakaoka S., Asai Y., Watashi K. and Iwami S.
  • Journal Title: Bulletin of Mathematical Biology Volume: 81(5) Issue: 5 Pages: 1427-1441
  • DOI: 10.1007/s11538-018-00564-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantitative immunology by data analysis using mathematical models (2019)
  • Author(s): S. Iwanami and S. Iwami
  • Journal Title: Encyclopedia of Bioinformatics and Computational Biology Volume: 2 Pages: 984-992
  • DOI: 10.1016/b978-0-12-809633-8.20250-1
  • ISBN: 9780128114322
  • Peer Reviewed
• [Journal Article] Dynamics of HIV-1 coinfection in different susceptible target cell populations during cell-free infection (2018)
  • Author(s): Y. Ito, A. Tauzin, A. Remion, K. Ejima, F. Mammano and S. Iwami
  • Journal Title: Journal of Theoretical Biology Volume: 455 Pages: 39-46
  • DOI: 10.1016/j.jtbi.2018.06.025
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A PDE multiscale model of hepatitis C virus infection can be transformed to a system of ODEs (2018)
  • Author(s): K. Kitagawa, S. Nakaoka, Y. Asai, K. Watashi, S. Iwami
  • Journal Title: Journal of Theoretical Biology Volume: 48 Pages: 80-85
  • DOI: 10.1016/j.jtbi.2018.04.006
  • Peer Reviewed / Open Access
• [Journal Article] Malaria incidences in South Africa linked to a climate mode in southwestern Indian Ocean (2018)
  • Author(s): SK. Behera, Y. Morioka, T. Ikeda, T. Doi, JV. Ratnam, M. Nonaka, A. Tsuzuki, C. Imai, Y. Kim, M. Hashizume, S. Iwami, P. Kruger, R. Maharaj, N. Sweijd and N. Minakawa
  • Journal Title: Environmental Development Volume: 27 Pages: 47-57
  • DOI: 10.1016/j.envdev.2018.07.002
  • Peer Reviewed / 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] Number of infection events per cell during HIV-1 cell-free infection (2017)
  • Author(s): Ito Y, Remion A, Tauzin A, Ejima K, Nakaoka S, Iwasa Y, Iwami S, Mammano F
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 6559-6559
  • DOI: 10.1038/s41598-017-03954-9
  • 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] A highly pathogenic simian/human immunodeficiency virus effectively produces infectious virions compared with a less pathogenic virus in cell culture (2017)
  • Author(s): Iwanami S, Kakizoe Y, Morita S, Miura T, Nakaoka S, Iwami S
  • Journal Title: Theor Biol Med Model Volume: 14 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s12976-017-0055-8
  • NAID: 120006305768
  • Peer Reviewed / Open Access
• [Journal Article] A heart-brain-kidney network controls adaptation to cardiac stress through tissue macrophage activation and cellular communication (2017)
  • Author(s): Fujiu K, Shibata M, Nakayama Y, Ogata F, Matsumoto S, Noshita K, Iwami S, Nakae S, Komuro I, Nagai R, Manabe I
  • Journal Title: Nature Medicine Volume: 印刷中 Issue: 5 Pages: 611-622
  • DOI: 10.1038/nm.4326
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection (2017)
  • Author(s): Y. Koizumi, H. Ohashi, S. Nakajima, Y. Tanaka, T. Wakita, AS. Perelson, S. Iwami†, and K. Watashi†.
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 114 Pages: 1922-1927
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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, and S. Iwami
  • Journal Title: Scientific Reports Volume: 7 Pages: 42765-42765
  • NAID: 120005997746
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A heart-brain-kidney network controls adaptation to cardiac stress through tissue macrophage activation and cellular communication (2017)
  • Author(s): K. Fujiu†, M. Shibata†, Y. Nakayama, F. Ogata, S. Matsumoto, K. Noshita, S. Iwami, S. Nakae, I. Komuro, R. Nagai, and I. Manabe
  • Journal Title: Nature Medicine Volume: in press
  • Peer Reviewed
• [Journal Article] (In)validating experimentally-derived knowledge about influenza A defective interfering particles (2016)
  • Author(s): LE. Liao, S. Iwami, CA. Beauchemin.
  • Journal Title: Journal of the Royal Society Interface Volume: 13 Pages: 20160412-20160412
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of asymptomatic infections on the early spread of malaria (2016)
  • Author(s): T. Funo, H. Inaba, M. Jusup, A. Tsuzuki, N. Minakawa, and S. Iwami
  • Journal Title: Japan Journal of Industrial and Applied Mathematics Volume: 33 Pages: 671-681
  • NAID: 210000176097
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Modelling Ebola virus dynamics: Implications for therapy (2016)
  • Author(s): A. Martyushev, S. Nakanoka, K. Sato, T. Noda†, and S. Iwami†.
  • Journal Title: Antiviral Research Volume: 135 Pages: 61-73
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Quantifying the effect of Vpu on the promotion of HIV-1 replication in the humanized mouse model (2016)
  • Author(s): H. Ikeda†, S Nakaoka†, RJ. De Boer, S. Morita, N. Misawa, Y. Koyanagi, K. Aihara, K. Sato‡, and S. Iwami‡
  • Journal Title: Retrovirology Volume: 13 Pages: 2-2
  • NAID: 120006353849
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamics of HIV infection in lymphoid tissue network (2016)
  • Author(s): S. Nakaoka, S. Iwami, and K. Sato
  • Journal Title: Journal of Mathematical Biology Volume: 72 Pages: 909-938
• [Journal Article] Quantifying the effect of Vpu on the promotion of HIV-1 replication in the humanized mouse model (2016)
  • Author(s): H. Ikeda, S Nakaoka, RJ. De Boer, S. Morita, N. Misawa, Y. Koyanagi, K. Aihara, K. Sato, and S. Iwami
  • Journal Title: Retrovirology Volume: -
  • NAID: 120006353849
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comment: Dynamically rich, yet parameter-sparse models for spatial epidemiology Comment on “Coupled disease-behavior dynamics on complex networks: A review”by Z. Wang et al. (2015)
  • Author(s): M. Jusup, S. Iwami, B. Podobnik, and E. Stanley
  • Journal Title: Physics of Life Reviews Volume: 15 Pages: 43-46
  • DOI: 10.1016/j.plrev.2015.09.006
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Exploring the conserved quantity of viral infection model with periodical cell removal (2015)
  • Author(s): Y. Kakizoe, and S. Iwami
  • Journal Title: Japan Journal of Industrial and Applied Mathematics Volume: 32 Pages: 1-9
  • NAID: 210000180589
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cell-to-cell infection by HIV contributes over half of virus infection (2015)
  • Author(s): Shingo Iwami, Junko S. Takeuchi, Shinji Nakaoka, Fabrizio Mammano, François Clavel, Hisashi Inaba, Tomoko Kobayashi, Naoko Misawa, Kazuyuki Aihara, Yoshio Koyanagi & Kei Sato
  • Journal Title: eLife Volume: 4 Pages: 1-16
  • DOI: 10.7554/elife.08150
  • NAID: 120005997708
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pandemic HIV-1 Vpu overcomes intrinsic herd immunity mediated by tetherin (2015)
  • Author(s): Shingo Iwami, Kei Sato, Satoru Morita, Hisashi Inaba, Tomoko Kobayashi, Junko S. Takeuchi, Yuichi Kimura, Naoko Misawa, Fengrong Ren, Yoh Iwasa, Kazuyuki Aihara & Yoshio Koyanagi
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 12256-12256
  • DOI: 10.1038/srep12256
  • NAID: 120005774579
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection (2018)
  • Author(s): Shingo Iwami
  • Organizer: ECMTB2018
  • Int'l Joint Research
• [Presentation] PKPDVD modeling for multi-drug treatment on HCV infection (2018)
  • Author(s): Shingo Iwami
  • Organizer: KSIAM2018SMB
  • Int'l Joint Research / Invited
• [Presentation] Characterizing SHIV infection in vitro and in vivo (2018)
  • Author(s): Shingo Iwami
  • Organizer: &JSMB2018
  • Int'l Joint Research
• [Presentation] Quantification of virus infection in cell culture (2017)
  • Author(s): Shingo Iwami
  • Organizer: A3-NIMS joint workshop on mathematical biology
  • Int'l Joint Research / Invited
• [Presentation] Quantifying antiviral activity optimizes drug combinations against HCV infection (2017)
  • Author(s): Shingo Iwami
  • Organizer: The 18th RIES-HOKUDAI international symposium
  • Int'l Joint Research / Invited
• [Presentation] Modeling virus infection in cell culture (2017)
  • Author(s): Shingo Iwami
  • Organizer: Simons Semester on Mathematical Biology in Warsaw, Epi-workshop
  • Int'l Joint Research / Invited
• [Presentation] HCV entry inhibitors for optimally boosting direct-acting antiviral-based treatments (2017)
  • Author(s): Shingo Iwami
  • Organizer: Innovative Mathematical Modeling for the Analysis of Infectious Disease Data
  • Int'l Joint Research / Invited
• [Presentation] Modeling ebola virus dynamics Implications for therapy (2015)
  • Author(s): Shingo Iwami
  • Organizer: Innovative Mathematical Modeling for the Analysis of Infectious Disease Data
  • Place of Presentation: Sapporo
  • Year and Date: 2015-10-29
  • Int'l Joint Research / Invited
• [Presentation] Quantifying antiviral activity optimizes drug combinations against HCV infection (2015)
  • Author(s): Shingo Iwami
  • Organizer: HCV 2015
  • Place of Presentation: France
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Modeling ebola virus dynamics Implications for therapy (2015)
  • Author(s): Shingo Iwami
  • Organizer: Erice MatheCompEpi2015
  • Place of Presentation: Italy
  • Year and Date: 2015-08-30
  • Int'l Joint Research
• [Presentation] A conserved quantity of virus infection in cell culture (2015)
  • Author(s): Shingo Iwami
  • Organizer: JSMB-CJK
  • Place of Presentation: Kyoto
  • Year and Date: 2015-08-26
  • Int'l Joint Research
• [Presentation] Modeling ebola virus dynamics Implications for therapy (2015)
  • Author(s): Shingo Iwami
  • Organizer: JSMB-CJK
  • Place of Presentation: Kyoto
  • Year and Date: 2015-08-26
  • Int'l Joint Research
• [Presentation] Quantifying the antiviral effect of IFN on HIV-1 replication in cell culture (2015)
  • Author(s): Shingo Iwami
  • Organizer: JSMB-CJK
  • Place of Presentation: Kyoto
  • Year and Date: 2015-08-26
  • Int'l Joint Research
• [Presentation] Quantifying combination activity of anti-HCV drugs in vitro (2015)
  • Author(s): Shingo Iwami
  • Organizer: 2nd WORKSHOP ON VIRUS DYNAMICS
  • Place of Presentation: Canada
  • Year and Date: 2015-07-17
  • Int'l Joint Research / Invited
• [Book] 日本生態学会編 シリーズ現在の生態学 6巻 「感染症の生態学」 “第23章 ＡＩＤＳ” (2016)
  • Author(s): 岩見真吾
  • Total Pages: 11
  • Publisher: 共立出版
• [Book] 日本生態学会編 シリーズ現在の生態学 1巻 「集団生物学」 “第5章 感染症動態” (2015)
  • Author(s): 岩見真吾
  • Total Pages: 13
  • Publisher: 共立出版