新規低分子化合物による抗HIV‐1中和抗体感受性の特異的増強とメカニズムの解析

2010 年度 研究成果報告書

• 研究課題/領域番号: 20591206
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 感染症内科学
• 研究機関: 熊本大学
• 研究代表者: 吉村 和久 熊本大学, エイズ学研究センター, 准教授 (60315306)
• 研究期間 (年度): 2008 – 2010
• キーワード: HIV-1 / 中和抗体 / 低分子化合物 / NBD-556 / gp120 / 中和抗体増強剤

研究概要

低分子化合物NBD-556は、CD4が結合したときと同様にgp120の立体構造を大きく変化させ、中和単クローン抗体の反応性を著しく増強することをこの基盤研究により証明した。NBD-556存在下では、中和単クローン抗体だけでなく、患者血清IgGで同時期に分離されたウイルスを中和できるようになる。これらの結果は、このNBD化合物が免疫増強作用を持つ低分子化合物として、新しい抗HIV治療の道を開くことが期待される。

研究成果

• [雑誌論文] CD4mimics targeting the HIV entry mechanism and their hybrid molecules with a CXCR4 antagonist. (2010)
  • 著者名/発表者名: Narumi, T., Ochiai, C., Yoshimura, K., Harada, S., Tanaka, T., Nomura, W., Arai, H., Ozaki, T., Ohashi, N., Matsushita, S., Tamamura, H.
  • 雑誌名: Bioorganic & Medicinal Chemistry Letters 20 ページ: 5853-5858
  • 査読あり
• [雑誌論文] Enhanced exposure of human immunodeficiency virus type 1 primary isolate neutralization epitopes through binding of CD4 mimetic compounds. (2010)
  • 著者名/発表者名: Yoshimura, K., Harada, S., Shibata, J., Hatada, M., Yamada, Y., Ochiai, C., Tamamura, H., Matsushita, S.
  • 雑誌名: J Virol 84 ページ: 7558-7568
  • 査読あり
• [雑誌論文] HIV-1 evasion of a neutralizing anti-V3 antibody involves acquisition of a potential glycosylation site in V2. (2010)
  • 著者名/発表者名: Hatada, M., Yoshimura, K., Harada, S., Kawanami, Y., Shibata, J., Matsushita, S.
  • 雑誌名: J Gen Virol 91 ページ: 1335-1345
  • 査読あり
• [雑誌論文] CD4 mimics targeting the mechanism of HIV entry. (2010)
  • 著者名/発表者名: Yamada, Y., Ochiai, C., Yoshimura, K., Tanaka, T., Ohashi, N., Narumi, T., Nomura, W., Harada, S., Matsushita, S., Tamamura, H.
  • 雑誌名: Bioorganic & Medicinal Chemistry Letters 20 ページ: 354-358
  • 査読あり
• [雑誌論文] Non-cleavage site gag mutations in amprenavir-resistant HIV-1 predispose HIV-1 to rapid acquisition of amprenavir resistance but delays development of resistance to other protease Inhibitors. (2009)
  • 著者名/発表者名: Aoki, M., Venzon, D.J., Koh, Y., Aoki-Ogata, H., Miyakawa, T., Yoshimura, K., Maeda, K., Mitsuya, H.
  • 雑誌名: J Virol. 83 ページ: 3059-3068
  • 査読あり
• [雑誌論文] SOCS1 is an inducible host factor during HIV-1 infection the intracellular trafficking and stability of HIV-1 Gag. (2008)
  • 著者名/発表者名: Ryo, A., Tsurutani, N., Ohba, K., Kimura, R., Komano, J., Nishi, M., Soeda, H., Hattori, S., Perrem, K., Yamamoto, M., Chiba, J., Mimaya, J., Yoshimura, K., Matsushita, S., Honda, M., Yoshimura, A., Sawasaki, T., Aoki, I., Morikawa, Y., Yamamoto, N.
  • 雑誌名: Proc Natl Acad Sci USA. 105 ページ: 294-299
  • 査読あり
• [学会発表] Evolution and selection of the env gene of HIV-1 primary isolates during in vitro selection of raltegravir. (2010)
  • 著者名/発表者名: Harada S., Hamji A., Matsushita S., Yoshimura K.
  • 学会等名: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • 発表場所: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
  • 年月日: 20101006-20101008
• [学会発表] Impact of a point mutation in V2 (L175P) in neutralization resistance mediated by functional trimer formation of Env. (2010)
  • 著者名/発表者名: Liu M., Shibata J., Harada S., Takehisa J., Yoshimura K., Matsushita S.
  • 学会等名: AIDS Vaccine 2010
  • 発表場所: The Omni Hotel at CNN Center, Atlanta, USA.
  • 年月日: 20100928-20101001
• [学会発表] CD4 mimetic compound-mediated enhancement of the neutralization activities of anti-V3 and CD4i monoclonal antibodies against the standard panel of primary isolates. (2010)
  • 著者名/発表者名: Matsushita S., Mouri S., Harada S., Yamada Y., Tamamura H., Yoshimura K.
  • 学会等名: XVIII International AIDS conference
  • 発表場所: The Reed Messe Wien, Vienna, Austria.
  • 年月日: 20100718-20100723
• [学会発表] In vitro selections of raltegravir resistant variants using diverse primary isolates, subtype B, C, CRFO1_AE, and CRFO8_BC. (2010)
  • 著者名/発表者名: Harada S., Yoshimura K., Kawanami Y., Matsushita S.
  • 学会等名: 2010 IYIS
  • 発表場所: The Center for AIDS Research, Kumamoto, Japan.
  • 年月日: 20100304-20100305
• [学会発表] Two step escape pathway of the HIV-1 subtype C primary isolate induced by the in vitro selection of Maraviroc. (2010)
  • 著者名/発表者名: Yoshimura K., Harada S., Matsushita S.
  • 学会等名: 17h Conference on Retroviruses and Opportunistic Infections (CROI 2010)
  • 発表場所: Moscone Center West, San Francisco, USA.
  • 年月日: 20100216-20100219
• [学会発表] A primary R5 isolate undergoes different escape pathway during in vitro selection with low or high concentration of an anti-V3 monoclonal antibody. (2009)
  • 著者名/発表者名: Narahara C., Hatada M., Harada S., Yoshimura K., Matsushita S.
  • 学会等名: AIDS Vaccine 2009 Conference
  • 発表場所: Marriott Rive Gauche Conference Center, Paris, France.
  • 年月日: 20091019-20091022
• [学会発表] Mechanism of maintaining a glycan-insertion in HIV-1 gp120 V2 region under pressure of a potent neutralizing antibody in vitro. (2009)
  • 著者名/発表者名: Matsushita S., Narahara C., Nishida Y., Honda A., Harada S., Yoshimura K.
  • 学会等名: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • 発表場所: Hotel Nikko Kumamoto, Japan.
  • 年月日: 20090928-20090929
• [学会発表] Mutations in gp120 of R5 HIV-1 laboratory isolate induced by the in vitro selection of maraviroc confer highly sensitive to anti-V3 monoclonal antibody. (2009)
  • 著者名/発表者名: Ishikawa T., Yoshimura K., Hatada M., Harada S., Matsushita S.
  • 学会等名: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • 発表場所: Hotel Nikko Kumamoto, Japan.
  • 年月日: 20090928-20090929
• [学会発表] In vitro induction of HIV-1 resistant to a CCR5 antagonist maraviroc. (2009)
  • 著者名/発表者名: Yoshimura K., Harada S., Hatada M., Matsushita S.
  • 学会等名: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • 発表場所: Hotel Nikko Kumamoto, Japan.
  • 年月日: 20090928-20090929
• [学会発表] Generation of an integrase inhibitor raltegravir resistant variants using recent primary isolates, X4, R5 and dual/mix HIV-1. (2009)
  • 著者名/発表者名: Harada S., Yoshimura K., Matsushita S.
  • 学会等名: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • 発表場所: Hotel Nikko Kumamoto, Japan.
  • 年月日: 20090928-20090929
• [学会発表] Polyclonal antibody response against gp120 including antibodies to V3, CD4bs and CD4i epitopes account or broad neutralization. (2009)
  • 著者名/発表者名: Matsushita S., Narahara C., Morizono M., Nishida Y., Honda-Shibata A., Harada S., Yoshimura, K.
  • 学会等名: 5th Conference on HIV Pathogenesis, Treatment and Prevention
  • 発表場所: The Cape Town International Convention Centre, Cape Town, South Africa.
  • 年月日: 20090719-20090722
• [学会発表] Mutations in V4 and C4 regions of the HIV-1 CRFO8-BC envelope induced by the in vitro selection of Maraviroc Confer cross-resistance to other CCR5 inhibitors. (2009)
  • 著者名/発表者名: Yoshimura K., Harada S., Hatada M., Matsushita S.
  • 学会等名: 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
  • 発表場所: Palais des Congres de Montreal, Montreal, Canada.
  • 年月日: 20090208-20090211
• [学会発表] In vitro induction of HIV-1 resistant to a CCR5. (2009)
  • 著者名/発表者名: Yoshimura K., Matsushita S.
  • 学会等名: Kumamoto AIDS Seminar GCOE Joint InternationalSymposium-Satellite Symposium
  • 発表場所: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
  • 年月日: 2009-09-30
• [学会発表] Different mutation in HIV-1 gp120 V3-tip region for escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection with low or high concentration of the Mab. (2008)
  • 著者名/発表者名: Narahara C., Yoshimura K., Hatada M., Harada S., Matsushita S.
  • 学会等名: 9th Kumamoto AIDS Seminar
  • 発表場所: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
  • 年月日: 20080918-20080919
• [学会発表] The impact of an N-linked glycosylation site insertion in HIV-1 gp120 region to escape from a potent neutralization anti-V3 monoclonal antibody. (2008)
  • 著者名/発表者名: Hatada M., Yoshimura K., Ishikawa T., Harada S., Matsushita S.
  • 学会等名: 9th Kumamoto AIDS Seminar
  • 発表場所: Aso Resort Grandvrio Hotel Kumamoto, Japan.
  • 年月日: 20080918-20080919
• [学会発表] In vitro induction of human immunodeficiency virus type 1 variants resistant to a low-molecular CD4 mimic compound. (2008)
  • 著者名/発表者名: Yoshimura K., Hatada M., Harada S., Shibata J., Masuno H., Tamamura H., Matsushita S.
  • 学会等名: 9th Kumamoto AIDS Seminar
  • 発表場所: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
  • 年月日: 20080918-20080919
• [備考] ホームページ等
  • URL: http://yoshimura-project.p1.bindsite.jp/