Empirical study on the formation of AIDS pathogenesis by primate model

• Project/Area Number: 16H04682
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory animal science
• Research Institution: Kyoto University
• Principal Investigator: MIURA Tomoyuki 京都大学, ウイルス・再生医科学研究所, 准教授 (40202337)
• Co-Investigator(Renkei-kenkyūsha): IWAMI Shingo 九州大学, 理学研究院, 准教授 (90518119)
• Research Collaborator: KAWAKAMI Akihiko ; MATSUURA Kanako
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2018: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2016: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: HIV / SHIV / アカゲザル / 動物モデル / 感染症 / エイズ

Outline of Final Research Achievements

Highly pathogenic SHIV was inoculated into rhesus macaques, and antiviral agents were administered to acute and chronic monkeys, respectively, and the attenuation of the amount of virus in blood observed with blocking new infections was measured. From the results obtained, the half-life of infected lymphocytes and infected macrophages was calculated by mathematical model analysis. Based on this information, the amount of macrophage-derived virus in the total amount of virus in the body was estimated. We have clarified the antiviral effect of current antiviral drugs on infected macrophages at individual level. It was examined histochemically whether macrophages function as virus reservoirs under antiviral therapy.

Academic Significance and Societal Importance of the Research Achievements

抗HIV薬の開発の過程ではウイルスのリンパ球への感染の阻止が指標として用いられており、マクロファージへの感染阻止および感染マクロファージへの抗ウイルス効果等はこれまでに検索されていない。このように個体レベルで未だ誰も検討していない問題に注目した点が独創的である。本研究計画が解明したHIV感染症におけるマクロファージ感染の意義は、実際の感染個体で得られる知見であるため、現行のヒトの多剤併用療法下で顕在化した諸問題へのマクロファージの関与を考えるうえで直接的かつ重要な基盤的情報となるものと考えられる。

Research Products

• [Journal Article] Induction of neutralizing antibodies against tier 2 human immunodeficiency virus 1 in rhesus macaques infected with tier 1B simian/human immunodeficiency virus (2019)
  • Author(s): Himeno Ai、Ishida Yuki、Mori Hiromi、Matsuura Kanako、Kikukawa Minako、Sakawaki Hiromi、Miura Tomoyuki
  • Journal Title: Archives of Virology Volume: 164 Issue: 5 Pages: 1297-1308
  • DOI: 10.1007/s00705-019-04173-5
  • Peer Reviewed / Open Access
• [Journal Article] Experimental infection of Japanese macaques with simian retrovirus 5 (2019)
  • Author(s): Koide Rie、Yoshikawa Rokusuke、Okamoto Munehiro、Sakaguchi Shoichi、Suzuki Juri、Isa Tadashi、Nakagawa So、Sakawaki Hiromi、Miura Tomoyuki、Miyazawa Takayuki
  • Journal Title: Journal of General Virology Volume: 100 Issue: 2 Pages: 266-277
  • DOI: 10.1099/jgv.0.001199
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Macaca radiata as a non-human primate model of Dengue virus infection. (2018)
  • Author(s): Kato Fumihiro, Ishida Yuki, Kawakami Akihiko, Takasaki Tomohiko, Saijo Masayuki, Miura Tomoyuki, Hishiki Takayuki.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 3421-3421
  • DOI: 10.1038/s41598-018-21582-9
  • NAID: 120006523833
  • Peer Reviewed / Open Access
• [Journal Article] CXCR4- and CCR5-tropic HIV-1 clones are both tractable to grow in rhesus macaques. (2018)
  • Author(s): Doi N, Miura T, Mori H, Sakawaki H, Koma T, Adachi A, and Nomaguchi M.
  • Journal Title: Frontiers in Microbiology Volume: 9 Pages: 2510-2510
  • DOI: 10.3389/fmicb.2018.02510
  • NAID: 120006937677
  • Peer Reviewed / Open Access
• [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] 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] In vivo virulence of MHC-adapted AIDS virus serially-passaged through MHC-mismatched hosts (2017)
  • Author(s): Seki Sayuri、Nomura Takushi、Nishizawa Masako、Yamamoto Hiroyuki、Ishii Hiroshi、Matsuoka Saori、Shiino Teiichiro、Sato Hironori、Mizuta Kazuta、Sakawaki Hiromi、Miura Tomoyuki、Naruse Taeko K.、Kimura Akinori、Matano Tetsuro
  • Journal Title: PLOS Pathogens Volume: 13 Issue: 9 Pages: e1006638-e1006638
  • DOI: 10.1371/journal.ppat.1006638
  • Peer Reviewed / Open Access
• [Journal Article] Hirsutine, an Indole Alkaloid of Uncaria rhynchophylla, Inhibits Late Step in Dengue Virus Lifecycle (2017)
  • Author(s): Hishiki Takayuki、Kato Fumihiro、Tajima Shigeru、Toume Kazufumi、Umezaki Masahito、Takasaki Tomohiko、Miura Tomoyuki
  • Journal Title: Frontiers in Microbiology Volume: 8 Pages: 1674-1674
  • DOI: 10.3389/fmicb.2017.01674
  • Peer Reviewed / Open Access
• [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., and Iwami, S.
  • Journal Title: Theoretical Biology and Medical Modelling Volume: 印刷中
  • NAID: 120006305768
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Generation of a neutralization-resistant CCR5 tropic SHIV-MK38 molecular clone, a derivative of SHIV-89.6. (2016)
  • Author(s): Ishida Yuki, Yoneda Mai, Otsuki Hiroyuki, Watanabe Yuji, Kato Fumihiro, Matuura Kanako, Kikukawa Minako, Matsushita Shuzo, Hishiki Takayuki, Igarashi Tatsuhiko, Miura Tomoyuki.
  • Journal Title: J Gen Virol Volume: 97(5) Issue: 5 Pages: 1249-60
  • DOI: 10.1099/jgv.0.000421
  • Peer Reviewed / Open Access
• [Journal Article] A minimally cytotoxic CD4 mimic as an HIV entry inhibitor (2016)
  • Author(s): Takaaki Mizuguchi, Shigeyoshi Harada, Tomoyuki Miura, Nami Ohashi, Tetsuo Narumi, Hiromi Mori, Yu Irahara, Yuko Yamada, Wataru Nomura, Shuzo Matsushita, Kazuhisa Yoshimura, Hirokazu Tamamura
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 26 Issue: 2 Pages: 397-400
  • DOI: 10.1016/j.bmcl.2015.11.103
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 霊長類モデルを用いたHIV感染症の予防・治療法開発 (2016)
  • Author(s): 三浦智行
  • Journal Title: 公益社団法人日本実験動物学会編: 実験動物感染症と感染症動物モデルの現状 Volume: - Pages: 99-105
• [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 Issue: 1 Pages: 30153-30153
  • DOI: 10.1038/srep30153
  • NAID: 120006346255
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Tier1B SHIV感染ザルにおける抗HIV-1 Tier2中和抗体の誘導 (2019)
  • Author(s): 姫野愛、石田裕樹、森ひろみ、松浦嘉奈子、菊川美奈子、阪脇廣美、三浦智行
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] SIV感染サル化マウスのAIDS病態モデルとしての有用性の検討 (2019)
  • Author(s): 横山温香、陣野萌恵、関根将、三浦智行、伊吹謙太郎
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] ワクチンによって誘導されたGagエピトープ特異的CD8陽性T細胞の交差性 (2019)
  • Author(s): 野村拓志、寺原和孝、石井洋、山本浩之、三浦智行、俣野哲朗
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] Protective effects of immunization using urease-deficient BCG, vaccinia LC16m8d, and Sendai virus expressing SIV genes (2019)
  • Author(s): Shida, H., Kato, S., Okamura, T., Mukai, T., Inoue, M., Shu, T., Miura, T., Yasutomi, Y., Matsuo, K.
  • Organizer: 第66回日本ウイルス学会学術集会
• [Presentation] 霊長類モデルを用いたHIV感染症の予防・治療法開発 (2017)
  • Author(s): 三浦智行
  • Organizer: 第26回サル疾病ワークショップ
• [Presentation] CCR5指向性サル/ヒト免疫不全ウイルス感染アカゲザル血漿における中和能の進化 (2017)
  • Author(s): 姫野愛、石田裕樹、森ひろみ、松浦嘉奈子、菊川美奈子、三浦智行
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] Induction of mutant epitope-specific CD8+ T cells is an indicator of the beginning of viral control failure in SIV controllers (2017)
  • Author(s): Nomura, T., Ishii, H., Seki, S., Yamamoto, H., Terahara, K., Miura, T., and Matano, T.
  • Organizer: 35th Annual Symposium on Nonhuman Primate Models for AIDS
  • Int'l Joint Research
• [Presentation] 免疫不全ウイルス感染病態研究におけるサル化マウスの有用性の検討 (2017)
  • Author(s): 陣野萌恵、関根将、横山温香、三浦智行、伊吹謙太郎
  • Organizer: 第65回日本ウイルス学会学術集会
• [Presentation] SIV感染サルをモデルとした中和抗体誘導メカニズムの解析 (2017)
  • Author(s): 桑田岳夫、佐野雅人、松岡佐織、俣野哲朗、関洋平、明里宏文、三浦智行、松下修三
  • Organizer: 第31回日本エイズ学会学術集会
• [Presentation] 中和抵抗性CCR5指向性サル/ヒト免疫不全ウイルス感染アカゲザル血漿における中和能の広域化 (2016)
  • Author(s): 姫野愛、石田裕樹、米田舞、松浦嘉奈子、菊川美奈子、三浦智行
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-23
• [Presentation] 中和抵抗性かつCCR5指向性の新規HIV-1rmtの構築 (2016)
  • Author(s): 川上朗彦、姫野愛、菊川美奈子、石田裕樹、野間口雅子、足立昭夫、三浦智行
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-23
• [Presentation] 中和感受性株SIVsmH635FC感染における中和抵抗性株SIVsmE543交差性中和抗体誘導の経時的解析 (2016)
  • Author(s): 佐野雅人、桑田岳夫、松岡佐織、関塚剛史、明里宏文、三浦智行、俣野哲朗
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-23
• [Presentation] カニクイザルにおけるR5指向性HIV-1長期潜伏感染の解析 (2016)
  • Author(s): Seki, Y., Saito, A., Satou, Y., Harada, S., Yoshimura, K., Ode, H., Iwatani, Y., Yoshida, T., Murata, M., Watanabe, Y., Yasutomi, Y., Matano, T., Miura, T., Akari, H.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-23
• [Presentation] HIV-１ワクチン開発とその課題 (2016)
  • Author(s): 志田壽利、加藤誠一、保富康宏、松尾和浩、三浦智行、五十嵐樹彦、張険峰、井上誠、成瀬妙子、木村彰方
  • Organizer: 第25回日本組織適合性学会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-22
  • Invited