Analysis of viral infection and innate immune response using humanized mice

• Project/Area Number: 24390112
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Virology
• Research Institution: Kyoto University
• Principal Investigator: KOYANAGI Yoshio 京都大学, ウイルス研究所, 教授 (80215417)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2013: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: ヒト化マウス / ウイルス制御因子 / HIV / tetherin / APOBEC3 / アクセサリ蛋白質 / Vif / シチジン脱アミノ酵素 / Vpr / 制御性T細胞 / Treg / HTLV

Outline of Final Research Achievements

Using a human hematopoietic stem cell-transplanted humanized mouse model, we found a series of HIV-1 infection mechanisms. Vpu contributes to efficient spread of HIV-1 in vivo. Vpu concomitantly downregulates tetherin and CD4 from the surface of infected cells. Vpr induces depletion of CCR5+ FOXP3+ CD4+ regulatory T cells （Treg） for enhancing viremia of CCR5-tropic HIV-1. APOBEC3F and APOBEC3G fundamentally work as restriction factors against HIV-1 in vivo, but at the same time, that APOBEC3F are capable of promoting viral diversification and evolution in vivo.

Research Products

• [Journal Article] Quantification of deaminase activity-dependent and -independent restriction of HIV-1 replication mediated by APOBEC3F and APOBEC3G through experimental-mathematical investigation. (2014)
  • Author(s): Kobayashi T, Koizumi Y, Takeuchi J, Misawa N, Kimura Y, Morita S, Aihara K, Koyanagi Y, Iwami S, Sato K
  • Journal Title: J Virol. Volume: 88 Issue: 10 Pages: 5881-5887
  • DOI: 10.1128/jvi.00062-14
  • Peer Reviewed
• [Journal Article] APOBEC3D and APOBEC3F Potently Promote HIV-1 Diversification and Evolution in Humanized Mouse Model (2014)
  • Author(s): Sato, K. Takeuchi, J. S. Misawa, N. Izumi, T. Kobayashi, T. Kimura, Y. Iwami, S. Takaori-Kondo, A. Hu, W. S. Aihara, K. Ito, M. An, D. S. Pathak, V. K. Koyanagi, Y.
  • Journal Title: PLoS Pathog Volume: 10 Issue: 10 Pages: e1004453-e1004453
  • DOI: 10.1371/journal.ppat.1004453
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] HIV-1 Vpr accelerates viral replication during acute infection by exploitation of proliferating CD4+ T cells in vivo (2013)
  • Author(s): Sato K., Misawa N., Iwami S., Satou Y., Matsuoka M., Ishizaka Y., Ito M., Aihara K., An D.S., Koyanagi Y.
  • Journal Title: PLoS Pathog. Volume: 9
  • Peer Reviewed
• [Journal Article] Antimicrobial peptide LL-37 produced by HSV-2-infected keratinocytes enhances HIV infection of Langerhans cells (2013)
  • Author(s): Ogawa Y, Kawamura T, Matsuzawa T, Aoki R, Gee P, Yamashita A, Moriishi K, Yamasaki K, Koyanagi Y. Blauvelt A, Shimada S.
  • Journal Title: Cell Host and Microbe Volume: 13 Issue: 1 Pages: 77-86
  • DOI: 10.1016/j.chom.2012.12.002
  • Peer Reviewed
• [Journal Article] Harnessing the CRISPR/Cas9 system to disrupt latent HIV-1 provirus. (2013)
  • Author(s): Ebina H, Misawa N, Kanemura Y, Koyanagi Y.
  • Journal Title: Sci. Rep. Volume: 3 Issue: 1 Pages: 2510-2510
  • DOI: 10.1038/srep02510
  • NAID: 120005324896
  • Peer Reviewed
• [Journal Article] Host factor SAMHD1 restricts DNA viruses in non-dividing myeloid cells (2013)
  • Author(s): Hollenbaugh J.A., Gee P., Baker J., Daly M.B., Amie S., Kasai N., Kanemura Y., Ward B.M., Koyanagi Y., Kim B.
  • Journal Title: PLoS Pathog. Volume: 9
  • Peer Reviewed
• [Journal Article] Functional antagonism of rhesus macaque and chimpanzee BST-2 by HIV-1 vpu is mediated by cytoplasmic domain interactions. (2013)
  • Author(s): Yoshida T, Koyanagi Y, Strebel K.
  • Journal Title: J Virol. Volume: 87 Issue: 24 Pages: 13825-13836
  • DOI: 10.1128/jvi.02567-13
  • Peer Reviewed
• [Journal Article] Oral administration of the CCR5 inhibitor , maraviroc, blocks HIV ex vivo infection of Langerhans cells within the epithelium (2013)
  • Author(s): Matsuzawa T, Kawamura T, Ogawa Y, Takahashi M, Aoki R, Moriishi K, Koyanagi Y, Gatanaga H, Blauvelt A, Shimada S
  • Journal Title: J Invest Dermatol Volume: 133(12) Issue: 12 Pages: 2803-5
  • DOI: 10.1038/jid.2013.215
  • Peer Reviewed
• [Journal Article] Vpu augments the initial burst phase of HIV-1 propagation and downre gulates BST2 and CD4 in humanized mice (2012)
  • Author(s): Sato, K.
  • Journal Title: J Virol. Volume: 86 Issue: 9 Pages: 5000-5013
  • DOI: 10.1128/jvi.07062-11
  • Peer Reviewed
• [Journal Article] Integrase-independent HIV-1 infection is augmented under conditions of DNA damage and produces a viral reservoir (2012)
  • Author(s): Ebina H, Kanemura Y, Suzuki Y, Urata K, Misawa N, Koyanagi Y
  • Journal Title: Virology Volume: 427 Issue: 1 Pages: 44-50
  • DOI: 10.1016/j.virol.2012.02.004
  • NAID: 120004007474
  • Peer Reviewed
• [Journal Article] Vpu and BST2: still not there yet? (2012)
  • Author(s): Sato K., Gee P., Koyanagi Y.
  • Journal Title: Frontiers in Microbiology Volume: 3 Pages: 131-131
  • DOI: 10.3389/fmicb.2012.00131
  • Peer Reviewed
• [Presentation] ヒト化マウスモデルを用いたエイズウイルス適応進化メカニズムの解明 (2014)
  • Author(s): 佐藤佳, 竹内（柴田）潤子, 小林朋子, 三沢尚子, 山田英里, 中野雄介, 吉川禄助, 小柳義夫
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Conflicts and benefits between primate lentiviruses and host restriction factors (2014)
  • Author(s): Koyanagi, Y., Sato, K.
  • Organizer: 15th Kumamoto AIDS Seminar
  • Place of Presentation: Kumamoto
  • Year and Date: 2014-10-01 – 2014-10-03
  • Invited
• [Presentation] レンチウイルスと宿主の進化的軍拡競争の分子メカニズム (2014)
  • Author(s): 佐藤佳, 竹内（柴田）潤子, 小林朋子, 吉川禄助, 山田英里, 中野雄介, 任鳳蓉, 田中博, 小柳義夫
  • Organizer: 日本進化学会第16回大会
  • Place of Presentation: 高槻
  • Year and Date: 2014-08-22
  • Invited
• [Presentation] HIV strategy for acceleration of viral replication in vivo and eradication approach of HIV proviral DNA (2014)
  • Author(s): Koyanagi Y., Misawa N., Sato K., Ebina H.
  • Organizer: 9th International Symposium of the Institute Network
  • Place of Presentation: Osaka
  • Year and Date: 2014-06-18 – 2014-06-19
  • Invited
• [Presentation] APOBEC3F potently promotes HIV-1 diversification and evolution in humanized mouse model (2014)
  • Author(s): Sato, K., Shibata, J., Izumi, T., Misawa, N., Kobayashi, T., Kimura, Y., Ito, M., Pathak, V. K., Koyanagi, Y.
  • Organizer: Cold Spring Harbor Laboratory Meeting on Retroviruses
  • Place of Presentation: New York
  • Year and Date: 2014-05-19 – 2014-05-24
• [Presentation] Differential impact of HIV-1 G-to-A hypermutation Induced by APOBEC3G and APOBEC3F in vivo (2013)
  • Author(s): Sato K., Shibata J., Izumi T., Misawa N., Kobayashi T., Kimura Y., Ito M., Pathak K.V., Koyanagi Y.
  • Organizer: 38th Retroviruses Meeting Cold Spring Harbor
  • Place of Presentation: Cold Spring Harbor, New York, USA
• [Presentation] Intrinsic cellular defenses against retroviruses and DNA viruses (2013)
  • Author(s): Koyanagi Y
  • Organizer: 12th Awaji International Forum on Infection and Immunity (AIFII 12)
  • Place of Presentation: Awaji, Japan
  • Invited
• [Presentation] Strategy of disrupting latent form of HIV-1 proviral DNA (2013)
  • Author(s): Koyanagi Y
  • Organizer: 14th Kumamoto AIDS Seminar
  • Place of Presentation: Kumamoto, Japan
  • Invited
• [Presentation] HIV strategy for acceleration of viral replication in vivo and eradication approach of HIV proviral DNA (2013)
  • Author(s): Koyanagi, Y. Misawa N., Sato K., Ebina H
  • Organizer: Japan-Russia International Workshop
  • Place of Presentation: Kyoto, Japan
  • Invited
• [Presentation] Overview of infection model of humanized mice (2012)
  • Author(s): Koyanagi Y,
  • Organizer: 1st Samsung Humanized Mice Symposium
  • Place of Presentation: Seoul(Korea)(招待講演)
  • Year and Date: 2012-04-14
• [Book] Humanized Mice for HIV Research (2014)
  • Author(s): Poluektova, L.Y., Garcia, J.V., Koyanagi, Y., Manz, M.G., Tager, A.M. (Eds.)
  • Total Pages: 537
  • Publisher: Springer
• [Remarks] 京都大学ウイルス研究所annual report 2013
  • URL: http://www.virus.kyoto-u.ac.jp/about/data2013/AR2013_full.pdf
• [Remarks] 京都大学ウイルス研究所ウイルス病態研究領域ホームページ
  • URL: http://www.virus.kyoto-u.ac.jp/Lab/KoyanagiHP/
• [Remarks] 京都大学ウイルス研究所年報
  • URL: http://www.virus.kyoto-u.ac.jp/about/data2012/AR2012_full.pdf
• [Remarks]
  • URL: http://www.virus.kyoto-u.ac.jp/about/data2011/AR2011_full.pdf