Development of vaccine that induces neutralizing antibodies to HIV-1

• Project/Area Number: 18591119
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kumamoto University
• Principal Investigator: MATSUSHITA Shuzo Kumamoto University, エイズ学研究センター, 教授 (00199788)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,100,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥600,000); Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
• Keywords: ウイルス / 感染症 / 内科 / 免疫学 / HIV / 中和抗体 / ワクチン開発 / AIDSワクチン

Research Abstract

HIV-1感染を阻止する中和抗体の誘導を目的としたワクチン候補の探索が世界的に行われているが、いまだに有効な方法の報告はない。我々は、様々な中和単クローン抗体を用い、その中和能やgp120への反応性を検討した。その結果、CD4bs抗体の0.5δが単独でgp120に立体構造変化を起こしV3抗体の反応性を飛躍的に増強することを見出した。この結果はgp120とCD4bs抗体複合体の免疫源としての可能性を示唆する。

Research Products

• [Journal Article] The anti-retroviral potency of APOBECl deaminase from small animal species (2009)
  • Author(s): Ikeda, T.
  • Journal Title: Nucleic Acids Research 36 Pages: 6859-6871
  • Peer Reviewed
• [Journal Article] SOCS1 is an inducible host factor during HIV-1 infection the intracellular trafficking and stability of HIV-1 Gag (2008)
  • Author(s): Ryo, A., Tsurutani, N., Ohba, K., Kimura, R., Komano, J., Nishi, M., Hiromi Soeda, 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.
  • Journal Title: Proc Natl Acad Sci U S A 105 Pages: 294-299
• [Journal Article] The anti-retroviral potency of APOBEC1 deaminase from small animal species (2008)
  • Author(s): Ikeda, T., Ohsugi, T., Kimura, T., Matsushita, S., Maeda, Y., Harada, S., Koito, A.
  • Journal Title: Nucleic Acids Research 36(21) Pages: 6859-6871
• [Journal Article] SOCS1 is an inducible host factor during HIV-1 infection the intracellular trafficking and stability of HIV-1 Gag. (2008)
  • Author(s): Ryo, A.
  • Journal Title: Proc Natl Acad Sci USA. 105 Pages: 294-299
  • Peer Reviewed
• [Journal Article] SOCS1 is an inducible host factor during HIV-1 infection and regulates the intracellular trafficking and stability of HIV-1 Gag. (2008)
  • Author(s): Ryo, A.
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 294-299
  • Peer Reviewed
• [Journal Article] Recurrent HIV-1 integration at the BACH2 locus in resting CD4+ T cell populations during effective HAART (2007)
  • Author(s): Ikeda, T., Shibata, J., Yoshimura, K., Koito, K., Matsushita, S.
  • Journal Title: J. Infect. Dis 195 Pages: 716-725
• [Journal Article] Impact of V2 mutations for escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection of a primary HIV-1 isolate (2007)
  • Author(s): Shibata, J., Yoshimura, K., Honda, A., Koito, A., Murakami, T., Matsushita, S.
  • Journal Title: J. Virol 81 Pages: 3757-3768
• [Journal Article] Wild type and H43Y variant of human TRIM5α show similar anti-human immunodeficiency virus type 1 activity both in vivo and in vitro (2007)
  • Author(s): Nakayama, E.E., Carpentier, W., Costagliola, D., Shioda, T., Iwamoto, A., Debre, P, Yoshimura, K., Autran, B., Matsushita, S., Theodorou, I
  • Journal Title: Immunogenetics 59 Pages: 511-515
• [Journal Article] Successful efavirenz dose reduction in HIV-1-infeccted individuals with cytochrome P450 2B6*6 and *26 (2007)
  • Author(s): Gatanaga, H., Hayashida, T., Tsuchiya, K., Yoshino, M., Kuwahara, T., Tsukada, H., Fujimoto, K., Sato, I., Ueda, M., Horiba, M., Hamaguchi, M., Yamamoto, M., Takata, N., Kimura, A., Koike, T., Gejyo, F., Matsushita, S., Shirasaka,T., Kimura, S., Oka, S.
  • Journal Title: Clinical Infectious Diseases 45 Pages: 1230-1237
• [Journal Article] Impact of V2 mutations on escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection of a primary human immunodeficiency virus type 1 isolate (2007)
  • Author(s): Shibata, J.
  • Journal Title: Journal of Virology 81 Pages: 3757-3768
  • Peer Reviewed
• [Journal Article] Wild type and H43Y variant of human TRIM5 α show similar anti-human immunodeficiency virus type 1 activity both in vivo and in vitro. (2007)
  • Author(s): Nakayama, E.E
  • Journal Title: Immunogenetics 59 Pages: 511-515
  • Peer Reviewed
• [Journal Article] Successful efavirenz dose reduction in HIV-1-infeccted individuals with cytochrome P450 2B*6 and *26. (2007)
  • Author(s): Gatanaga, H.
  • Journal Title: Clin Infec Dis. 45 Pages: 1230-1237
  • Peer Reviewed
• [Journal Article] Recurrent HIV-1 integration at the BACH2 locus in resting CD4+ T cell populations during effective HAART. (2007)
  • Author(s): Ikeda, T.
  • Journal Title: J.Infect.Dis. 195 Pages: 716-725
• [Journal Article] Impact of V2 mutations for escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection of a primary HIV-1 isolate. (2007)
  • Author(s): Shibata, J.
  • Journal Title: J.Virol. in press
• [Journal Article] Sequential immunization with V3 peptides from primary HIV-1 produces cross-neutralizing antibodies against primary isolates with matching narrow neutralization sequence motif (2006)
  • Author(s): Eda, Y., Takizawa, M., Murakami, T., Maeda, H., Kimachi, K., Yonemura, H., Koyanagi, S., Shiosaki, K., Higuchi, H., Makizumi, K., Nakashima, T., Osatomi, K., Tokiyoshi, S., Matsushita, S., Yamamoto, N., Honda, M
  • Journal Title: J. Virol 80 Pages: 5552-5562
• [Journal Article] Anti-V3 humanized antibody KD-247 effectively suppresses ex vivo generation of human immunodeficiency virus type 1 and affords sterile protection of monkeys against a heterologous simian/human immunodeficiency virus infection (2006)
  • Author(s): Eda, Y., Murakami, T., Ami, Y., Nakasone, T., Takizawa, M., Someya, K., Kaizu, M., Izumi, Y., Yoshino, N., Matsushita, S., Higuchi, H., Matsui, H., Shinohara, K., Takeuchi, H., Koyanagi, S., Yamamoto, N., Honda M.
  • Journal Title: J. Virol 80 Pages: 5563-5570
• [Journal Article] Resistance profile of a novelbroadly neutralizing anti-HIV monoclonal antibody, KD-247, thatshows favorable synergism withanti-CCR5 inhibitors in vitro (2006)
  • Author(s): Yoshimura, K., Shibata, J., Kimura, T.,Honda, A., Maeda, Y., Koito, A.,Murakami, T., Mitsuya, H., Matsushita,S
  • Journal Title: AIDS 20 Pages: 2065-2073
• [Journal Article] Sequential immunization with V3 peptides from primary HIV-1 produces cross-neutralizing antibodies against primary isolates with matching narrow neutralization sequence motif. (2006)
  • Author(s): Eda, Y.
  • Journal Title: J.Virol 80 Pages: 5552-5562
• [Journal Article] Anti-V3 humanized antibody KD-247 effectively suppresses ex vivo generation of human immunodeficiency virus type 1 and affords sterile protection of monkeys against a heterologous simian/human immunodeficiency virus infection. (2006)
  • Author(s): Eda, Y.
  • Journal Title: J.Virol 80 Pages: 5563-5570
• [Journal Article] Resistance profile of a novel broadly neutralizing anti-HIV monoclonal antibody, KD-247, that shows favorable synergism with anti-CCR5 inhibitors in vitro. (2006)
  • Author(s): Yoshimura, K.
  • Journal Title: AIDS 20 Pages: 2065-2073
• [Presentation] Mutations in V4 and C4 regions of the HIV-1 CRF-BC envelope induced by the in vitro selection of Maraviroc Confer cross-resistance to other CCR5 inhibitors (2009)
  • Author(s): Yoshimura, K., Harada S., Hatada, M., Matsushita, S.
  • Organizer: 16th Conference on Trtroviruses and Opportunistic Infections(CROI 2009)
  • Place of Presentation: Montreal, Canada
• [Presentation] Impact of V2 mutations for escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection of a primary HIV-1 isolate (2009)
  • Author(s): Shibata, J., Yoshimura, K., Honda, A., Koito, A., Murakami, T., Matsushita, S.
  • Organizer: 7th AIDS Seminar in Kumamoto
• [Presentation] Mutations in V4 and C4 regions of the HIV-1 CRF-BC envelope induced by the in vitro selection of Maraviroc Confer cross-resistance to other CCR5 inhibitors. (2009)
  • Author(s): Yoshimura, K
  • Organizer: 16th Conference on Trtroviruses and Opportunistic Infections
  • Place of Presentation: Montreal, Canada.
• [Presentation] In vitro induction of human immunodeficienby virus type 1 variants resistant to a low-molecular CD4 mimic compound. (2008)
  • Author(s): Yoshimura, K.
  • Organizer: 9^<th> Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto.
  • Year and Date: 2008-09-18
• [Presentation] CD4 mimic small compoundのin vitro耐性誘導による結合部位の予測 (2008)
  • Author(s): 吉村和久、原田恵嘉、畑田万紀子、増野弘幸、玉村啓和、松下修三
  • Organizer: 第22回日本エイズ学会学術集会・総会
  • Place of Presentation: 大阪
• [Presentation] V2領域のN-glycosylation site挿入が抗V3中和抗体エスケープに及ぼす影響 (2008)
  • Author(s): 畑田万紀子、吉村和久、石川哲也、原田恵嘉、松下修三
  • Organizer: 第22回日本エイズ学会学術集会・総会
  • Place of Presentation: 大阪
• [Presentation] 中和抗体高感受性R5臨床分離株の抗V3抗体によるin vitro中和逃避ウイルス誘導 (2008)
  • Author(s): 楢原知里、吉村和久、畑田万紀子、原田恵嘉、松下修三
  • Organizer: 第22回日本エイズ学会学術集会・総会
  • Place of Presentation: 大阪
• [Presentation] Broad cross-neutralization mediated by combination of anti-V3 and CD4 binding site antibodies in an HIV-1 infected patient with long-term non-progressie disease (2008)
  • Author(s): Matsushita, S., Nishida, Y., Shibata J., Honda A., Yoshimura, K
  • Organizer: 15th Conference on Retroviruses and Opportunistic infections
  • Place of Presentation: Boston, USA
• [Presentation] In vitro induction of human immunodeficienby virus type 1 variants resistant to a low-molecular CD4 mimic compound, N-(4-Chlorophenyl)-N'-(2, 2, 6, 6-tetramethylpiperidin-4-yl)-oxalamide (NBD-556) (2008)
  • Author(s): Yoshimura, K., Shibata J., Honda, A., Yamada, Y., Nasuo, H., Tamamura, H., Matsushita, S.
  • Organizer: 15th Conference on Retroviruses and Opportunistic infections
  • Place of Presentation: Boston, USA
• [Presentation] In vitro induction of human immunodeficienby virus type 1 variants resistant to a low-molecular CD4 mimic compound (2008)
  • Author(s): Yoshimura, K., Hatada, M., Harada, S., Shibata, J., Masuo, H., Tamamura, H., Matsushita, S.
  • Organizer: 9^<th> Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto
• [Presentation] 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)
  • Author(s): Hatada, M., Yoshimura, K, Ishikawa, T., Harada, S., Matsushita, S.
  • Organizer: 9^<th> Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto
• [Presentation] Different mutation in HIV-1 gp120 V3-tip regin for escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection with low or high concentration of the Mab (2008)
  • Author(s): Narahara, C., Yoshimura, K., Hatada, M., Harada, S., Matsushita, S.
  • Organizer: 9^<th> Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto
• [Presentation] CD4 mimic small compoundとanti-HIV monoclonal antibodyのウイルス中和における相乗効果 (2008)
  • Author(s): 吉村和久、柴田潤二、畑田万紀子、山田裕子、増野弘幸、玉村啓和、松下修三
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島
• [Presentation] 長期間HAART有効症例における残存HIVと組込み部位の関連性 (2008)
  • Author(s): 池田輝政、柴田潤二、吉村和久、小糸厚、松下修三
  • Organizer: 第54回日本ウイルス学会総会
  • Place of Presentation: 名古屋
• [Presentation] The impact of an N-linked glycosylation site insertion in HIV-1gp120 region to escape from a potent neutralization anti-V3 monoclonal antibody. (2008)
  • Author(s): Hatada, M.
  • Organizer: 9^<th> Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto.
• [Presentation] Different mutation in HIV-1 gpl20 V3-tip regin for escape from a potent neutralizing anti-V3 monoclonal antibody during in vitro selection with low or high concentration of the Mab. (2008)
  • Author(s): Narahara C.
  • Organizer: 9^<th> Kumamoto AIDS Seminar
  • Place of Presentation: Aso, Kumamoto.
• [Presentation] CD4 mimic small compoundのin vitro耐性誘導による結合部位の予測 (2008)
  • Author(s): 吉村和久
  • Organizer: 第22回日本エイズ学会学術集会・総会.
  • Place of Presentation: 大阪
• [Presentation] V2領域のN-glycosylation site挿入が抗V3中和抗体エスケープに及ぼす影響. (2008)
  • Author(s): 畑田万紀子
  • Organizer: 第22回日本エイズ学会学術集会・総会.
  • Place of Presentation: 大阪
• [Presentation] 中和抗体高感受性R5臨床分離株の抗V3抗体によるin vitro中和逃避ウイルス誘導. (2008)
  • Author(s): 楢原知里
  • Organizer: 第22回日本エイズ学会学術集会・総会
  • Place of Presentation: 大阪
• [Presentation] 長期非進行症例 (LTNP) における交叉中和のメカニズムの研究 I; 中和単クローン抗体の作成と解析 (2007)
  • Author(s): 松下 修三
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島県広島市
  • Year and Date: 2007-11-28
• [Presentation] 長期非進行症例 (LTNP) における交叉中和のメカニズムの研究 II; 中和単クローン抗体のsubtype B panelに対する交差中和活性 (2007)
  • Author(s): 西田 吉辰
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島県広島市
  • Year and Date: 2007-11-28
• [Presentation] 強力な抗HIV-1 gp120-V3抗体KD-247に対するHIV-1BaLの中和逃避のメカニズム解析 (2007)
  • Author(s): 畑田 万紀子
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島県広島市
  • Year and Date: 2007-11-28
• [Presentation] 中和抗体高度抵抗性ウイルスを感受性にする変異はgp120三量体構造に影響を与える (2007)
  • Author(s): 柴田 潤二
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島県広島市
  • Year and Date: 2007-11-28
• [Presentation] CD4 mimic small compoundとanti-HIV monoclonal antibodyのウイルス中和における相乗効果 (2007)
  • Author(s): 吉村 和久
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島県広島市国際会議場
  • Year and Date: 2007-11-28
• [Presentation] Development of broadly reactive neutralizing monoclonal antibody KD-247: implications for passive immunotherapy (2007)
  • Author(s): Matsushita, S.
  • Organizer: 3rd Japan-Germany HIV/AIDS Symposium
  • Place of Presentation: Hiroshima.
  • Year and Date: 2007-11-26
• [Presentation] 長期非進行症例(LTNP)における交叉中和のメカニズムの研究I ; 中和単クローン抗体の作成と解析 (2007)
  • Author(s): 松下修三、西田吉辰、柴田潤二、畑田万紀子、吉村和久
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島
• [Presentation] 長期非進行症例(LTNP)における交叉中和のメカニズムの研究II ; 中和単クローン抗体のsubtype B panelに対する交差中和活性 (2007)
  • Author(s): 西田吉辰、柴田潤二、吉村和久, 松下修三
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島
• [Presentation] 強力な抗HIV-1 gp120-V3抗体KD-247に対するHIV-1BaLの中和逃避のメカニズム解析 (2007)
  • Author(s): 畑田万紀子, 吉村和久, 柴田潤二, 松下修三
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島
• [Presentation] 中和抗体高度抵抗性ウイルスを感受性にする変異はgp120三量体構造に影響を与える (2007)
  • Author(s): 柴田潤二、吉村和久、松下修三
  • Organizer: 第21回日本エイズ学会学術集会・総会
  • Place of Presentation: 広島
• [Presentation] Persistence of proviral DNA and the integration sites of HIV-1 in patients on prolonged and effective HAART (2007)
  • Author(s): Matsushita, S.
  • Organizer: 4^<th> IAS Conference on HIV Pathogenesis, Treatment and Prevention.
  • Place of Presentation: Sydney,Australia.
• [Presentation] A potent neutralizing anti-V3 monoclonal antibody, KD-247 shows favorable synergism with other antiretrovirals, sCD4 and CD4 mimic small compound in vitro (2007)
  • Author(s): Yoshimura, K.
  • Organizer: 4^<th> IAS Conference on HIV Pathogenesis, Treatment and Prevention.
  • Place of Presentation: Sydney,Australia.
• [Presentation] 抗HIV-1 gp120-V3抗体より逃避したV2領域変異ウイルスの中和抵抗性メカニズムの解析 (2006)
  • Author(s): 柴田潤二、吉村和久、小糸厚、松下修三
  • Organizer: 第54回日本ウイルス学会総会
  • Place of Presentation: 名古屋
• [Presentation] In vitroにおける抗HIV-1中和単クローン抗体とその他の薬剤との相互作用の研究 (2006)
  • Author(s): 吉村和久、柴田潤二、小糸厚、松下修三
  • Organizer: 第20回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京
• [Presentation] シンポジウム3「より良いHAARTに向けて」-耐性検査の意義とタイミング (2006)
  • Author(s): 松下修三
  • Organizer: 第20回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京
• [Presentation] Development of broadly reactive neutralizing monoclonal antibody KD247 : implications for passive immunotherapy (2006)
  • Author(s): Matsushita, S., Shibata, J., Honda, A., Murakami, T., Eda, Y., Koito, A., Yoshimura, K.
  • Organizer: AIDS Vaccine 2006 Conference, Amsterdam, the Netherlands
• [Presentation] A Role of Mutations in Non-V3 Envelope Regions for Escape from a Broad Neutralizing Anti-V3 Monoclonal Antibody, KD-247, during in vitro Selection (2006)
  • Author(s): Shibata, J., Yoshimura, K., Honda A., Murakami, T., Koito, A., and Matsushita, S.
  • Organizer: 13th Conference on Retroviruses and Opportunistic Infections
  • Place of Presentation: Denver, USA
• [Presentation] Resistance Profile of A Novel Broadly Neutralizing Anti-HIV Monoclonal Antibody, KD-247 That Has Favorable Synergism with Anti-CCR5 Inhibitors In Vitro (2006)
  • Author(s): Yoshimura, K., Shibata, J., Honda A., Murakami, T., Mitsuya, H., Koito, A.,and and Matsushita, S.
  • Organizer: 13th Conference on Retroviruses and Opportunistic Infections
  • Place of Presentation: Denver, USA
• [Presentation] Recurrent HIV-1 integration at BACH2 locus in resting CD4+T cell populations during effective HAART (2006)
  • Author(s): Ikeda, T., Shibata, J., Yoshimura, K., Koito, A., Matsushita, S.
  • Organizer: 7th AIDS Seminar in Kumamoto
• [Remarks]
  • URL: http://www.caids.kumamoto-u.ac.jp/CLINICAL/default.html
• [Patent(Industrial Property Rights)] 抗HIVモノクローナル抗体 (2008)
  • Inventor(s): 松下修三
  • Industrial Property Rights Holder: 熊本大学
  • Filing Date: 2008-11-19
  • Overseas
• [Patent(Industrial Property Rights)] 抗HIVモノクローナル抗体 (2007)
  • Inventor(s): 松下修三
  • Industrial Property Rights Holder: 熊本大学
  • Industrial Property Number: 2007-299083
  • Filing Date: 2007-11-19
• [Patent(Industrial Property Rights)] 抗HIVモノクローナル抗体 (2007)
  • Inventor(s): 松下 修三
  • Industrial Property Rights Holder: 熊本大学
  • Filing Date: 2007-11-19