Mathematical modeling and analysis of virus-host interaction

2016 Fiscal Year Annual Research Report

• Project Area: Molecular basis of host cell competency in virus infection
• Project/Area Number: 24115008
• Research Institution: The Graduate University for Advanced Studies
• Principal Investigator: 佐々木 顕 総合研究大学院大学, 先導科学研究科, 教授 (90211937)
• Co-Investigator(Kenkyū-buntansha): 小柳 義夫 京都大学, ウイルス・再生医科学研究所, 教授 (80215417)
• Project Period (FY): 2012-06-28 – 2017-03-31
• Keywords: A3H多型 / Vif多型 / 感染実験 / R0中心性 / 感染部位ネットワーク / トロピズム / HIV / 宿主内感染ダイナミクス

Outline of Annual Research Achievements

抗原進化ダイナミクスのモデル化に関しては宿主免疫をエスケープする突然変異体の流行と宿主免疫獲得の連鎖を確率過程で表すことにより、流行型の年次変化幅、抗原空間における進化軌道の直進性、進路の角度分布についての理論的な結果を得た。

また、宿主内の複数の組織で増殖する能力をもつウイルスの動態を、それぞれの組織での増殖と、ウイルス粒子の組織間移動を取り入れたモデルとして解析した。宿主体内の多数の部位が複雑な移動経路でつながったネットワーク上で増殖するウイルスについて、その挙動や治療の効果を探るのは困難と思われてきたが、R0中心性の概念(Yashima and Sasaki 2016)と摂動展開を用いることにより、病原体が最も高い増殖率をもつ部位だけに集中的に介入する戦略が極めて有効であり、それ以外の部位への対策はほとんど効果がないこと等を解析的に明らかにした。

HIVに対する宿主防御因子APOBEC3 (A3)ファミリーのひとつであるA3H遺伝子には7つの遺伝子多型があるが、その形質は安定発現型（A3H+）と不安定型（A3H-）に大別され、A3H+は一部のHIV Vifに耐性を示す。一方、APOBEC3による抗ウイルス効果を相殺する機能を持つウイルスタンパク質であるVifは、A3H+を拮抗阻害できるHyper-Vifと、拮抗阻害できないhypo-Vifに大別され、その機能は39, 48番目のアミノ酸残基で規定されている。そこで、A3H多型とVif多型の進化的なダイナミズムを探るため、ヒト血液幹細胞移植マウスに野生型及びvif変異HIV-1の感染実験を行い、遺伝子多型解析を行った。その結果、A3H+は生体内HIV増殖を制御する宿主防御因子であること、A3H+存在下においてはHyper-Vifの機能が必須であることがわかった（Nakano et al, in prep）。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Partitioning light spectra: adaptive stratification of phytobenthic communities in Antarctic lakes (2017)
  • Author(s): Sasaki A, and Mizuno A
  • Journal Title: J Theor Biol Volume: in press Pages: -
  • DOI: 10.1016/j.jtbi.2017.04.022
  • Peer Reviewed
• [Journal Article] Functional mutations in spike glycoprotein of Zaire ebolavirus associated with an increase in infection efficiency. (2017)
  • Author(s): Ueda MT, Kurosaki Y, Izumi T, Nakano Y, Oloniniyi OK, Yasuda J, Koyanagi Y, Sato K, Nakagawa S.
  • Journal Title: Genes Cells. Volume: 22 Pages: 148-159
  • DOI: 10.1111/gtc.12463
  • Peer Reviewed
• [Journal Article] Feline immunodeficiency virus evolutionarily acquires two proteins, Vif and protease, capable of antagonizing feline APOBEC3. (2017)
  • Author(s): Yoshikawa R, Takeuchi J, Yamada E, Nakano Y, Misawa N, Kimura Y, Ren F, Miyazawa T, Koyanagi Y, Sato K.
  • Journal Title: J Virol Volume: JVI.00250-17 Pages: -
  • DOI: 10.1128/JVI.00250-17
  • Peer Reviewed
• [Journal Article] Various plus unique: Viral protein U as a plurifunctional protein for HIV-1 replication (2017)
  • Author(s): Soper A, Juarez-Fernandez G, Aso H, Moriwaki M, Yamada E, Nakano Y, Koyanagi Y, Sato K.
  • Journal Title: Exp Biol Med Volume: 242 Pages: 850-858
  • DOI: 10.1177/1535370217697384
  • Peer Reviewed / Open Access
• [Journal Article] HIV-1 competition experiments in humanized mice show that APOBEC3H imposes selective pressure and promotes virus adaptation. (2017)
  • Author(s): Nakano Y, Misawa N, Juarez-Fernandez G, Moriwaki M, Nakaoka S, Funo T, Yamada E, Soper A, Yoshikawa R, Ebrahimi D, Tachiki Y, Iwami S, Harris RS, Koyanagi Y, Sato K.
  • Journal Title: PLoS Pathogens Volume: in press Pages: -
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A conflict of interest: the evolutionary arms race between mammalian APOBEC3 and lentiviral Vif (2017)
  • Author(s): Nakano Y, Aso H, Soper A, Yamada E, Moriwaki M, Juarez-Fernandez G, Koyanagi Y, Sato K,
  • Journal Title: Retrovirology Volume: in press Pages: -
  • Peer Reviewed
• [Journal Article] Spotting epidemic keystones by R0 sensitivity analysis: High-risk stations in the Tokyo metropolitan area (2016)
  • Author(s): Yashima K, and Sasaki A
  • Journal Title: PLoS ONE Volume: 11:e0162406 Pages: -
  • DOI: 10.1371/journal.pone.0162406
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Evolutionary branching under multi-dimensional evolutionary constraints (2016)
  • Author(s): Ito H, and Sasaki A
  • Journal Title: J Theor Biol Volume: 407 Pages: 409-428
  • DOI: 10.1016/j.jtbi.2016.07.011
  • Peer Reviewed
• [Journal Article] Beyond pairs: Definition and interpretation of third-order structure in spatial point patterns (2016)
  • Author(s): Kaito C, Dieckmann U, Sasaki A, and Takasu F
  • Journal Title: J Theor Biol Volume: 372 Pages: 22-38
  • DOI: 10.1016/j.jtbi.2015.02.004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of RyDEN (C19orf66) as an interferon-stimulated cellular inhibitor against dengue virus replication. (2016)
  • Author(s): Suzuki Y, Chin WX, Han QE, Ichiyama K, Lee CH, Eyo WZ, Ebina E, Takahashi H, Takahashi C, Tan BH, Hishiki T, Ohba K, Matsuyama T, Koyanagi Y, Tan YJ, Sawasaki T, Chu JJH, Vasudevan SG, Sano K, Yamamoto N.
  • Journal Title: PLoS Pathogens Volume: 12:e1005357 Pages: -
  • DOI: 10.1371/journal.ppat.1005357
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Perspectives of genome-editing technologies 1 for HIV therapy. (2016)
  • Author(s): Ebina H, Gee P, Koyanagi Y
  • Journal Title: Curr HIV Res Volume: 14 Pages: 2-8
  • DOI: 10.2174/1570162X13666150807105718
  • Peer Reviewed
• [Journal Article] Species-specific differences in the ability of feline lentiviral Vif to degrade feline APOBEC3 proteins. (2016)
  • Author(s): Yoshikawa R, Nakano Y, Yamada E, Izumi T, Misawa N, Koyanagi Y, Sato K.
  • Journal Title: Microbiol Immunol Volume: 60 Pages: 272-279
  • DOI: 10.1111/1348-0421.12371
  • Peer Reviewed
• [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 Pages: 23
  • DOI: 10.1186/s12977-016-0252-2
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Small ruminant lentiviral Vif proteins commonly utilize cyclophilin A, an evolutionary and structurally conserved protein, to degrade ovine and caprine APOBEC3 proteins (2016)
  • Author(s): Yoshikawa R, Izumi T, Nakano Y, Yamada E, Moriwaki M, Misawa N, Ren F, Kobayashi T, Koyanagi Y, Sato K.
  • Journal Title: Microbiol Immunol Volume: 60 Pages: 427-436
  • DOI: 10.1111/1348-0421.12387.
  • Peer Reviewed
• [Journal Article] Insufficient anti-HIV-1 potency of the CRISPR/Cas9 system for full viral replication. (2016)
  • Author(s): Ueda S, Hirotaka Ebina H, Kanemura Y, Misawa N, Koyanagi Y,
  • Journal Title: Microbiol Immunol Volume: 60 Pages: 483-496
  • DOI: 10.1111/1348-0421.12395
  • Peer Reviewed
• [Journal Article] APOBEC3 proteins can copackage and comutate HIV-1 genomes. (2016)
  • Author(s): Desimmie BA, Burdick RC, Izumi T, Doi H, Shao W, Alvord WG, Sato K, Koyanagi Y, Jones S, Wilson E, Hill S, Maldarelli F, Hu WS, Pathak VK.
  • Journal Title: Nucleic Acids Res Volume: 44: Pages: 7848-7865
  • DOI: 10.1093/nar/gkw653
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Association of lymph-node antigens with lower Gag-specific central-memory and higher Env-specific effector-memory CD8(+) T-cell frequencies in a macaque AIDS model. (2016)
  • Author(s): Ishii H, Matsuoka S, Nomura T, Nakamura M, Shiino T, Sato Y, Iwata-Yoshikawa N, Hasegawa H, Mizuta K, Sakawaki H, Miura T, Koyanagi Y, Naruse TK, Kimura A, Matano T.
  • Journal Title: Sci Rep. Volume: 6:30153 Pages: -
  • DOI: 10.1038/srep30153
  • Peer Reviewed / Open Access
• [Journal Article] A naturally occurring bovine APOBEC3 confers resistance to bovine lentiviruses: implication for the co-evolution of bovids and their lentiviruses. (2016)
  • Author(s): Yamada E, Yoshikawa R, Nakano Y, Misawa N, Kobayashi T, Ren F, Izumi T, Miyazawa T, Koyanagi Y, Sato K.
  • Journal Title: Sci Rep Volume: 6:33988 Pages: -
  • DOI: 10.1038/srep33988
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Impact of endogenous APOBEC3H haplotypes on HIV-1 replication in vivo (2016)
  • Author(s): Nakano, Y., Moriwaki, M., Juarez-Fernandez, G., Yoshikawa, R., Yamada, E., Soper, A., Misawa, N., Sato, K. and Koyanagi, Y.
  • Organizer: 64th Annual Meeting of the Japanese Society for Virology
  • Place of Presentation: Sapporo
  • Year and Date: 2016-10-23
• [Presentation] Investigation of the interplay between cellular proteins and HIV-1-encoding proteins using humanized mouse model (2016)
  • Author(s): Sato, K.
  • Organizer: The 15th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji
  • Year and Date: 2016-09-08
• [Presentation] HIV-1 quickly overcomes anti-viral activity of APOBEC3H in vivo (2016)
  • Author(s): Nakano, Y., Moriwaki, M., Juarez-Fernandez, G., Yoshikawa, R., Yamada, E., Soper, A., Misawa, N., Sato, K. and Koyanagi, Y.
  • Organizer: The 15th Awaji International Forum on Infection and Immunity
  • Place of Presentation: Awaji
  • Year and Date: 2016-09-08
• [Presentation] Evolution of global and local viral infection in the structured SIS model. (2016)
  • Author(s): Koichi Saeki and Akira Sasaki
  • Organizer: The 26th annual meeting of the Japanese Society for Mathematical Biology
  • Place of Presentation: Kyushu University, Fukuoka
  • Year and Date: 2016-09-07 – 2016-09-09
• [Presentation] Resampling after discrimination destabilizes mutualism (2016)
  • Author(s): Yu Uchiumi, Hisashi Ohtsuki, and Akira Sasaki
  • Organizer: The 26th annual meeting of the Japanese Society for Mathematical Biology
  • Place of Presentation: Kyushu University, Fukuoka
  • Year and Date: 2016-09-07 – 2016-09-09
• [Presentation] A Bayesian updating model for the antigenic escapes of influenza virus subtypes (2016)
  • Author(s): Akira Sasaki
  • Organizer: The 26th annual meeting of the Japanese Society for Mathematical Biology
  • Place of Presentation: Kyushu University, Fukuoka
  • Year and Date: 2016-09-07 – 2016-09-09
• [Presentation] Evolution of vertical transmission of symbionts by reducing the rate of cell division (2016)
  • Author(s): Yu Uchiumi, Hisashi Ohtsuki, and Akira Sasaki
  • Organizer: The 26th annual meeting of the Japanese Society for Mathematical Biology
  • Place of Presentation: Kyushu University, Fukuoka
  • Year and Date: 2016-09-07 – 2016-09-09
• [Presentation] Network centrality measure based on sensitivity analysis of the basic reproductive ratio (2016)
  • Author(s): Kenta Yashima and Akira Sasaki
  • Organizer: The 26th annual meeting of the Japanese Society for Mathematical Biology
  • Place of Presentation: Kyushu University, Fukuoka
  • Year and Date: 2016-09-07 – 2016-09-09
• [Presentation] Hosts end up destabilizing horizontally transmitted mutualism by resampling new symbionts after discrimination (2016)
  • Author(s): Yu Uchiumi, Hisashi Ohtsuki, Akira Sasaki
  • Organizer: 10th European Conference on Mathematical & Theoretical Biology and SMB Annual Meeting
  • Place of Presentation: University of Nottingham, Nottingham, UK
  • Year and Date: 2016-07-11 – 2016-07-15
  • Int'l Joint Research
• [Book] 「感染症の生態学」第22章 ヒトのインフルエンザ (2016)
  • Author(s): 佐々木 顕
  • Total Pages: pp286-296
  • Publisher: 共立出版
• [Book] 「感染症の生態学」第10章 病原生物と宿主の進化． (2016)
  • Author(s): 加茂将史・佐々木 顕
  • Total Pages: pp132-156
  • Publisher: 共立出版