Countermeasure study on HIV Env diversity using library clinical isolates

• Project/Area Number: 15K08125
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: National Institute of Infectious Diseases
• Principal Investigator: Harada Shigeyoshi 国立感染症研究所, エイズ研究センター, 主任研究官 (30508643)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: HIV / AIDS / 抗HIV阻害剤 / 抗HIV療法 / 耐性誘導 / 臨床分離株

Outline of Final Research Achievements

The aim of study was to develop novel countermeasures against HIV-1 Env diversity using library for HIV-1 clinical isolates, chemical library for HIV-1 entry inhibitors, and in vitro selection system. We determined that the region of the HIV-1 gp120-gp41 quaternary interface that is a novel target for HIV-1 Env inhibitors. In addition, the Env diversity was decreased within clinical isolates when passaged in the presence of novel inhibitors during in vitro selection. Furthermore, we determined that combination strategies containing entry inhibitors and NAbs are likely to be efficient weapons against HIV-1. These findings can provide useful data to support the design and the development of new HIV-1 entry inhibitors against HIV-1 Env diversity.

Research Products

• [Journal Article] Driving HIV-1 into a vulnerable corner by taking advantage of viral adaptation and evolution. (2017)
  • Author(s): Shigeyoshi Harada and Kazuhisa Yoshimura
  • Journal Title: Frontiers in Microbiology. Volume: 8: 390 Pages: 390-390
  • DOI: 10.3389/fmicb.2017.00390
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Biphasic CD8+ T-Cell Defense in Simian Immunodeficiency Virus Control by Acute-Phase Passive Neutralizing Antibody Immunization (2016)
  • Author(s): Iseda S, Takahashi N, Poplimont H, Nomura T, Seki S, Nakane T, Nakamura M, Shi S, Ishii H, Furukawa S, Harada S, Naruse TK, Kimura A, Matano T, Yamamoto H
  • Journal Title: Journal of virology Volume: 90 Pages: 6276-6290
  • DOI: 10.1128/jvi.00557-16
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A novel dual luciferase assay for the simultaneous monitoring of HIV infection and cell viability. (2016)
  • Author(s): Mitsuki Y-y, Yamamoto T, Mizukoshi F, Momota M, Terahara K, Yoshimura K, Harada S, Tsunetsugu-Yokota Y
  • Journal Title: Journal of Virological Methods Volume: 231 Pages: 25-33
  • DOI: 10.1016/j.jviromet.2016.02.006
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Small Molecular CD4 Mimics Containing Mono-cyclohexyl Moieties as HIV Entry Inhibitors (2016)
  • Author(s): Nami Ohashi1, Shigeyoshi Harada, Takaaki Mizuguchi1, Yu Irahara1, Yuko Yamada, Misato Kotani, Wataru Nomura, Shuzo Matsushita, Kazuhisa Yoshimura, Hirokazu Tamamura.
  • Journal Title: ChemMedChem Volume: 19 Pages: 940-6
  • DOI: 10.1002/cmdc.201500590
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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: Bioorg Med Chem Lett. Volume: 26 Pages: 397-400
  • DOI: 10.1016/j.bmcl.2015.11.103
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impact of the Maraviroc-Resistant Mutation M434I in the C4 Region of HIV-1 gp120 on Sensitivity to Antibody-Mediated Neutralization (2016)
  • Author(s): Samatchaya Boonchawalit, Shigeyoshi Harada, Noriko Shirai, Hiroyuki Gatanaga, Shinichi Oka, Shuzo Matsushita, Kazuhisa Yoshimura.
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 69 Issue: 3 Pages: 236-243
  • DOI: 10.7883/yoken.jjid.2015.310 10.7883/yoken.JJID.2015.310
  • NAID: 130005151997
  • ISSN: 1344-6304, 1884-2836
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel mutant human immunodeficiency virus type 1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by random mutagenesis. (2016)
  • Author(s): M. Hashimoto, H. Nasser, F. Bhuyan, N. Kuse, Y. Satou, S. Harada, K. Yoshimura, J. Sakuragi, K. Monde, Y. Maeda, S. Welbourn, K. Strebel, E.W.A. El-Wahab, M. Miyazaki , S. Hattori, N. Chutiwitoonchai, M. Hiyoshi, S. Oka, M. Takiguchi, S. Suzu.
  • Journal Title: J Gen Virol. Volume: 195 Pages: 4341-4350
  • DOI: 10.4049/jimmunol.1500955
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Synergistic anti-HIV effect of combination of a novel entry inhibitor and NAbs (2018)
  • Author(s): HARADA S, MATANO T, YOSHIMURA K
  • Organizer: 20th International Conference on Emerging Infectious Diseases in the Pacific Rim and Meetings of the AIDS (Joint with Immunology Board)
  • Int'l Joint Research
• [Presentation] 網羅的Env標的阻害剤ライブラリーの構築-2 (2017)
  • Author(s): 原田恵嘉, 野村渉, 鳴海哲夫, 横山勝, 前田賢次, 林宏典, 紺野奇重, 引地優太, 佐藤裕徳, 玉村啓和, 俣野哲朗, 吉村和久
  • Organizer: 第31回日本エイズ学会学術集会・総会
• [Presentation] Identification of novel HIV-1 Env inhibitors by structure-based in silico screening (2017)
  • Author(s): HARADA S, YOKOYAMA M, OGIHARA K, HIKICHI Y, SATO H, NARUMI T, MATANO T, YOSHIMURA K
  • Organizer: 18th Kumamoto AIDS Seminar, Kumamoto
  • Int'l Joint Research
• [Presentation] Discovery of novel bifunctional HIV-1 entry inhibitors using structure-based in silico screening (2017)
  • Author(s): HARADA S, YOKOYAMA M, OGIHARA K, HIKICHI Y, SATO H, NARUMI T, MATANO T, YOSHIMURA K
  • Organizer: The 65th Annual Meeting of the Japanese Society for Virology
• [Presentation] Bi-functional entry inhibitors sensitize macaque-tropic human immunodeficiency virus type 1 (HIV-1mt) to antibodies generated in HIV-1mt-infected macaques (2017)
  • Author(s): HARADA S, HIKICHI Y, SEKI Y, SAITO A, YOSHIDA T, ODE H, IWATANI Y, YASUTOMI Y, MIURA T, MATANO T, AKARI H, YOSHIMURA K
  • Organizer: 35th Annual Symposium on Nonhuman Primate Models for AIDS (NHP2017)
  • Int'l Joint Research
• [Presentation] Synthesis and properties of novel soluble bifunctional CD4-mimetic small molecules containing pyridine moiety (2017)
  • Author(s): HARADA S, KONNO K, HIKICHI Y, MATSUOKA S, M ATANO T, TAMAMURA H, YOSHIMURA K
  • Organizer: 9th IAS Conference on HIV Science (IAS 2017)
  • Int'l Joint Research
• [Presentation] Identification of novel HIV-1 gp120 CD4 binding site inhibitors using structure-based in silico screening (2017)
  • Author(s): HARADA S, YOKOYAMA M, OGIHARA K, HIKICHI Y, SATO H, NARUMI T, MATANO T, YOSHIMURA K
  • Organizer: 42nd Annual Meeting of Cold Spring Harbor Laboratory on Retroviruses
  • Int'l Joint Research
• [Presentation] Bifunctional抗HIV侵入阻害剤ライブラリーの構築およびその最新知見 (2017)
  • Author(s): 原田恵嘉, 引地優太, 俣野哲朗, 吉村和久
  • Organizer: 第19回 白馬シンポジウム
• [Presentation] Structure-based virtual screeningによる新規bifunctional抗HIV侵入阻害剤の探索 (2017)
  • Author(s): 原田恵嘉, 荻原香澄, 横山勝, 引地優太, 佐藤裕徳, 俣野哲朗, 鳴海哲夫, 吉村和久
  • Organizer: 第27回 抗ウイルス療法学会総会,
• [Presentation] 網羅的Env標的阻害剤ライブラリーの構築-1 (2016)
  • Author(s): 原田恵嘉, 野村渉, 鳴海哲夫, 横山勝, 前田賢次, 林宏典, 荻原香澄, 石田有佑, 引地優太, 佐藤裕徳, 玉村啓和, 俣野哲朗, 吉村和久
  • Organizer: 第30回日本エイズ学会学術集会・総会
  • Place of Presentation: 鹿児島市
  • Year and Date: 2016-11-24
• [Presentation] 6.Detection of potency and breadth of anti-HIV-1 neutralizing antibodies in two macaque-tropic HIV-1 infected cynomolgus monkeys that were different response by CD8 depletion (2016)
  • Author(s): Shigeyoshi Harada, Akatsuki Saito, Yohei Seki, Yasuhiro Yasutomi, Tomoyuki Miura, Tetsuro Matano, Hirofumi Akari, Kazuhisa Yoshimura
  • Organizer: 2nd Kumamoto IRCMS International Symposium and 17th Kumamoto AIDS Seminar, Kumamoto
  • Place of Presentation: Kumamoto
  • Year and Date: 2016-10-31
  • Int'l Joint Research
• [Presentation] Development of novel bifunctional entry inhibitors that target non-CD4-binding site of HIV-1 (2016)
  • Author(s): Shigeyoshi Harada, Kasumi Ogihara, Yuta Hikichi, Tetsuro Matano, Tetsuo Narumi, Kazuhisa Yoshimura
  • Organizer: The 64th Annual Meeting of the Japanese Society for Virology
  • Place of Presentation: Sapporo
  • Year and Date: 2016-10-23
• [Presentation] Design, Synthesis, and Antiviral Activity of Novel Bifunctional CD4-Mimetic Small Molecules Containing Mono-Cyclohexyl Moieties, YIR-819 and YIR-821 (2016)
  • Author(s): Shigeyoshi Harada, Yu Irahara, Yuta Hikichi, Nami Ohashi, Wataru Nomura, Shuzo Matsushita, Tetsuro Matano, Hirokazu Tamamura, Kazuhisa Yoshimura
  • Organizer: HIVR4P 2016
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-10-17
  • Int'l Joint Research
• [Presentation] Comparison of plasma neutralizing antibodies in two macaque-tropic HIV-1 infected macaques that were different response by CD8 depletion (2016)
  • Author(s): Shigeyoshi Harada, Yohei Seki, Yasuhiro Yasutomi, Tomoyuki Miura, Tetsuro Matano, Hirofumi Akari, Kazuhisa Yoshimura
  • Organizer: 34th Annual Symposium on Nonhuman Primate Models for AIDS (NHP2016),
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-10-11
  • Int'l Joint Research
• [Presentation] 作用部位の異なるEnv標的阻害剤ライブラリーの構築およびその最新知見 (2016)
  • Author(s): 原田恵嘉, 引地優太, 俣野哲朗, 吉村和久
  • Organizer: 第18回 白馬シンポジウム
  • Place of Presentation: 山梨県北杜市
  • Year and Date: 2016-10-07
• [Presentation] CD4 mimicと結合領域が異なる新規bifunctional抗HIV侵入阻害剤の開発 (2016)
  • Author(s): 原田恵嘉, 荻原香澄, 俣野哲朗, 鳴海哲夫, 吉村和久
  • Organizer: 第26回 抗ウイルス療法学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Molecular Dynamics of the CD4-Mimetic Resistant HIV-1 Gp120 by MD Simulation (2016)
  • Author(s): Shigeyoshi Harada, Masaru Yokoyama, Shuzo Matsushita, Hironori Sato, Tetsuro Matano, Kazuhisa Yoshimura
  • Organizer: 23th Conference on Retroviruses and Opportunistic Infections (CROI 2016)
  • Place of Presentation: Boston, MA, U.S.A.
  • Year and Date: 2016-02-22
  • Int'l Joint Research
• [Presentation] CD4類似低分子化合物誘導体（CD4MCs）の耐性機序解析 (2015)
  • Author(s): 原田恵嘉、横山勝、佐藤裕徳、松下修三、俣野哲朗、玉村啓和、吉村和久
  • Organizer: 第29回 日本エイズ学会学術集会・総会
  • Place of Presentation: 東京
  • Year and Date: 2015-11-30
• [Presentation] Design, synthesis and virological evaluation of novel CD4-mimetic small molecules (2015)
  • Author(s): Shigeyoshi Harada, Yu Irahara, Hirokazu Tamamura, Shuzo Matsushita, Tetsuro Matano, Kazuhisa Yoshimura
  • Organizer: 第63回 日本ウイルス学会学術集会
  • Place of Presentation: 福岡市
  • Year and Date: 2015-11-22
• [Presentation] Detection of potency and breadth of HIV-1 neutralizing antibodies in macaque-tropic HIV-1 infected cynomolgus monkeys using novel test panel viruses (2015)
  • Author(s): Shigeyoshi Harada, Akatsuki Saito, Takeshi Yoshida, Yohei Seki, Yuji Watanabe, Yasumasa Iwatani, Yasuhiro Yasutomi, Tomoyuki Miura, Tetsuro Matano, Hirofumi Akari, Kazuhisa Yoshimura
  • Organizer: 33rd Annual Symposium on Nonhuman Primate Models for AIDS
  • Place of Presentation: Monterey, CA, U.S.A.
  • Year and Date: 2015-10-13
  • Int'l Joint Research
• [Presentation] Genetic and molecular dynamics studies of the NBD-556, YYA-021 and JRC-II-191 binding to the wild type and mutant HIV-1 gp120 (2015)
  • Author(s): Shigeyoshi Harada, Masaru Yokoyama, Shuzo Matsushita, Hironori Sato, Kazuhisa Yoshimura
  • Organizer: The 15th Kumamoto AIDS Seminar
  • Place of Presentation: 熊本県阿蘇市
  • Year and Date: 2015-10-07
  • Int'l Joint Research
• [Presentation] Shigeyoshi Harada, Yu Irahara, Hirokazu Tamamura, Tetsuro Matano, Shuzo Matsushita, Kazuhisa Yoshimura (2015)
  • Author(s): Novel CD4-mimetic small molecules show enhancement of the neutralization activity of anti-cryptic V3 neutralizing antibody, KD-247.
  • Organizer: 8th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2015)
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2015-07-19
  • Int'l Joint Research
• [Presentation] gp120相互作用強化型CD4ミミック化合物の開発 (2015)
  • Author(s): 原田恵嘉
  • Organizer: 第18回 日本レトロウイルス研究会 夏期セミナー
  • Place of Presentation: 名古屋
  • Year and Date: 2015-07-10
• [Presentation] Asp368およびVal430と相互作用を有する新規CD4類似低分子化合物の開発 (2015)
  • Author(s): 原田恵嘉、苛原優、玉村啓和、俣野哲朗、吉村和久
  • Organizer: 第17回 白馬シンポジウム
  • Place of Presentation: 鳥取県米子市
  • Year and Date: 2015-06-19
• [Presentation] Asp368およびVal430と相互作用を有する新規CD4類似低分子化合物の開発 (2015)
  • Author(s): 原田恵嘉、苛原優、玉村啓和、俣野哲朗、吉村和久
  • Organizer: 第25回 抗ウイルス療法学会総会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-22
• [Book] HIVエンベロープの治療標的構造研究：新規治療法における侵入阻害剤と中和抗体の関係 (2016)
  • Author(s): 原田恵嘉，吉村和久
  • Total Pages: 8
  • Publisher: 日本エイズ学会誌
• [Remarks] 吉村和久研究室
  • URL: http://www0.nih.go.jp/niid/arc-l1/index.html
• [Patent(Industrial Property Rights)] HIV感染阻害剤 (2015)
  • Inventor(s): 玉村啓和、野村渉、鳴海哲夫、松下修三、吉村和久、原田恵嘉、他
  • Industrial Property Rights Holder: 玉村啓和、野村渉、鳴海哲夫、松下修三、吉村和久、原田恵嘉、他
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-05-25