Analysis for a mechanism of anti-HIV-1 neutralizing antibody enhancement by a novel low molecular weight compound.

• Project/Area Number: 20591206
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: YOSHIMURA Kazuhisa Kumamoto University, エイズ学研究センター, 准教授 (60315306)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: HIV-1 / 中和抗体 / 低分子化合物 / NBD-556 / gp120 / 中和抗体増強剤 / エンベロープ

Research Abstract

Combinations of NBD-556 with anti-gp120 MAbs showed highly synergistic interactions against HIV-1. We further found that after enhancing the neutralizing activity by adding NBD-556, the contemporaneous virus became highly sensitive to antibodies in the patient's plasma. These findings suggest that small compounds such as NBDs may enhance the neutralizing activities of CD4i and anti-V3 Abs in vivo.

Research Products

• [Journal Article] CD4mimics targeting the HIV entry mechanism and their hybrid molecules with a CXCR4 antagonist. (2010)
  • Author(s): Narumi, T., Ochiai, C., Yoshimura, K., Harada, S., Tanaka, T., Nomura, W., Arai, H., Ozaki, T., Ohashi, N., Matsushita, S., Tamamura, H.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 20 Pages: 5853-5858
  • Peer Reviewed
• [Journal Article] Enhanced exposure of human immunodeficiency virus type 1 primary isolate neutralization epitopes through binding of CD4 mimetic compounds. (2010)
  • Author(s): Yoshimura, K., Harada, S., Shibata, J., Hatada, M., Yamada, Y., Ochiai, C., Tamamura, H., Matsushita, S.
  • Journal Title: J Virol 84 Pages: 7558-7568
  • Peer Reviewed
• [Journal Article] HIV-1 evasion of a neutralizing anti-V3 antibody involves acquisition of a potential glycosylation site in V2. (2010)
  • Author(s): Hatada, M., Yoshimura, K., Harada, S., Kawanami, Y., Shibata, J., Matsushita, S.
  • Journal Title: J Gen Virol 91 Pages: 1335-1345
  • Peer Reviewed
• [Journal Article] CD4 mimics targeting the mechanism of HIV entry. (2010)
  • Author(s): Yamada, Y., Ochiai, C., Yoshimura, K., Tanaka, T., Ohashi, N., Narumi, T., Nomura, W., Harada, S., Matsushita, S., Tamamura, H.
  • Journal Title: Bioorganic & Medicinal Chemistry Letters 20 Pages: 354-358
  • Peer Reviewed
• [Journal Article] Enhanced exposure of human immunodeficiency virus type 1 primary isolate neutralization epitopes through binding of CD4 mimetic compounds. (2010)
  • Author(s): Yoshimura, K.
  • Journal Title: J.Virol. Volume: 84 Pages: 7558-7568
  • Peer Reviewed
• [Journal Article] CD4mimics targeting the HIV entry mechanism and their hybrid molecules with a CXCR4 antagonist. (2010)
  • Author(s): Narumi, T.
  • Journal Title: Bioorg.Med.Chem.Lett. Volume: 20 Pages: 354-358
  • Peer Reviewed
• [Journal Article] CD4 mimics targeting the mechanism of HIV entry (2010)
  • Author(s): Yamada, Y.
  • Journal Title: Bioorg.Med.Chem.Lett. 20 Pages: 354-358
  • Peer Reviewed
• [Journal Article] HIV-1 evasion of a neutralizing anti-V3 antibody involves acquisition of a potential glycosylation site in V2 (2010)
  • Author(s): Hatada, M.
  • Journal Title: J.Gen.Virol. 91 Pages: 1335-1345
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Aoki, M., Venzon, D.J., Koh, Y., Aoki-Ogata, H., Miyakawa, T., Yoshimura, K., Maeda, K., Mitsuya, H.
  • Journal Title: J Virol. 83 Pages: 3059-3068
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Aoki, M.
  • Journal Title: J.Virol. 83 Pages: 3059-3068
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Aoki, M.
  • Journal Title: J. Virol. 83 Pages: 3059-3068
  • 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., 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.
  • 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 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
• [Presentation] Evolution and selection of the env gene of HIV-1 primary isolates during in vitro selection of raltegravir. (2010)
  • Author(s): Harada S., Hamji A., Matsushita S., Yoshimura K.
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
• [Presentation] Impact of a point mutation in V2 (L175P) in neutralization resistance mediated by functional trimer formation of Env. (2010)
  • Author(s): Liu M., Shibata J., Harada S., Takehisa J., Yoshimura K., Matsushita S.
  • Organizer: AIDS Vaccine 2010
  • Place of Presentation: The Omni Hotel at CNN Center, Atlanta, USA.
• [Presentation] CD4 mimetic compound-mediated enhancement of the neutralization activities of anti-V3 and CD4i monoclonal antibodies against the standard panel of primary isolates. (2010)
  • Author(s): Matsushita S., Mouri S., Harada S., Yamada Y., Tamamura H., Yoshimura K.
  • Organizer: XVIII International AIDS conference
  • Place of Presentation: The Reed Messe Wien, Vienna, Austria.
• [Presentation] In vitro selections of raltegravir resistant variants using diverse primary isolates, subtype B, C, CRFO1_AE, and CRFO8_BC. (2010)
  • Author(s): Harada S., Yoshimura K., Kawanami Y., Matsushita S.
  • Organizer: 2010 IYIS
  • Place of Presentation: The Center for AIDS Research, Kumamoto, Japan.
• [Presentation] Two step escape pathway of the HIV-1 subtype C primary isolate induced by the in vitro selection of Maraviroc. (2010)
  • Author(s): Yoshimura K., Harada S., Matsushita S.
  • Organizer: 17h Conference on Retroviruses and Opportunistic Infections (CROI 2010)
  • Place of Presentation: Moscone Center West, San Francisco, USA.
• [Presentation] Evolution and selection of the env gene of HIV-1 primary isolates during in vitroselection of raltegravir. (2010)
  • Author(s): Harada, S.
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Aso Resort Grandvrio Hotel, Kumamoto, Japan
• [Presentation] Impact of a point mutation in V2(L175P)in neutralization resistance mediated by functional trimer formation of Env. (2010)
  • Author(s): Liu, M.
  • Organizer: AIDS Vaccine Meeting 2010
  • Place of Presentation: The Omni Hotel at CNN, Center, Atlanta, USA
• [Presentation] CD4 mimetic compound-mediated enhancement of the neutralization activities of anti-V3 and CD4i monoclonal antibodies against the standard panel of primary isolates. (2010)
  • Author(s): Matsushita, S.
  • Organizer: XVIII International AIDS conference
  • Place of Presentation: The Reed Messe Wien, Vienna, Austria
• [Presentation] Two step escape pathway of the HIV-1 subtype C primary isolate induced by the in vitro selection of Maraviroc (2010)
  • Author(s): 吉村和久
  • Organizer: 17h Conference on Retroviruses and Opportunistic Infections(CROI 2010)
  • Place of Presentation: Moscone Center West, San Francisco, USA
• [Presentation] In vitro selections of raltegravir resistant variants using diverse primary isolates, subtype B, C, CRF01_AE, and CRF08_BC (2010)
  • Author(s): 原田恵嘉
  • Organizer: 2010 AIDS gCOE International Young Investigator Seminar(IYIS)
  • Place of Presentation: Center for AIDS Research, Kumamoto, Japan
• [Presentation] In vitro induction of HIV-1 resistant to a CCR5. (2009)
  • Author(s): Yoshimura K., Matsushita S.
  • Organizer: Kumamoto AIDS Seminar GCOE Joint InternationalSymposium-Satellite Symposium
  • Place of Presentation: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
  • Year and Date: 2009-09-30
• [Presentation] A primary R5 isolate undergoes different escape pathway during in vitro selection with low or high concentration of an anti-V3 monoclonal antibody. (2009)
  • Author(s): Narahara C., Hatada M., Harada S., Yoshimura K., Matsushita S.
  • Organizer: AIDS Vaccine 2009 Conference
  • Place of Presentation: Marriott Rive Gauche Conference Center, Paris, France.
• [Presentation] Mechanism of maintaining a glycan-insertion in HIV-1 gp120 V2 region under pressure of a potent neutralizing antibody in vitro. (2009)
  • Author(s): Matsushita S., Narahara C., Nishida Y., Honda A., Harada S., Yoshimura K.
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko Kumamoto, Japan.
• [Presentation] 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)
  • Author(s): Ishikawa T., Yoshimura K., Hatada M., Harada S., Matsushita S.
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko Kumamoto, Japan.
• [Presentation] In vitro induction of HIV-1 resistant to a CCR5 antagonist maraviroc. (2009)
  • Author(s): Yoshimura K., Harada S., Hatada M., Matsushita S.
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko Kumamoto, Japan.
• [Presentation] Generation of an integrase inhibitor raltegravir resistant variants using recent primary isolates, X4, R5 and dual/mix HIV-1. (2009)
  • Author(s): Harada S., Yoshimura K., Matsushita S.
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko Kumamoto, Japan.
• [Presentation] Polyclonal antibody response against gp120 including antibodies to V3, CD4bs and CD4i epitopes account or broad neutralization. (2009)
  • Author(s): Matsushita S., Narahara C., Morizono M., Nishida Y., Honda-Shibata A., Harada S., Yoshimura, K.
  • Organizer: 5th Conference on HIV Pathogenesis, Treatment and Prevention
  • Place of Presentation: The Cape Town International Convention Centre, Cape Town, South Africa.
• [Presentation] 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)
  • Author(s): Yoshimura K., Harada S., Hatada M., Matsushita S.
  • Organizer: 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
  • Place of Presentation: Palais des Congres de Montreal, Montreal, Canada.
• [Presentation] Polyclonal antibody response against gp120 including antibodies to V3, CD4bs and CD4i epitopes account or broad neutralization (2009)
  • Author(s): Matsushita, S.
  • Organizer: 5th Conference on HIV Pathogenesis, Treatment and Prevention
  • Place of Presentation: The Cape Town International Convention Centre(CTICC), Cape Town, South Africa.
• [Presentation] Mechanism of maintaining a glycan-insertion in HIV-1 gp120 V2 region under pressure of a potent neutralizing antibody in vitro (2009)
  • Author(s): 畑田万紀子
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko kumamoto, Kumamoto, Japan
• [Presentation] 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)
  • Author(s): 石川哲也
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko kumamoto, Kumamoto, Japan
• [Presentation] Generation of an integrase inhibitor raltegravir resistant variants using recent primary isolates, X4, R5 and dual/mix HIV-1 (2009)
  • Author(s): 原田惠嘉
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko kumamoto, Kumamoto, Japan
• [Presentation] In vitro induction of HIV-1 resistant to a CCR5 antagonist maraviroc (2009)
  • Author(s): 吉村和久
  • Organizer: 10th Kumamoto AIDS Seminar GCOE Joint International Symposium
  • Place of Presentation: Hotel Nikko kumamoto, Kumamoto, Japan
• [Presentation] A primary R5 isolate undergoes different escape pathway during in vitro selection with low or high concentration of an anti-V3 monoclonal antibody (2009)
  • Author(s): Narahara, C
  • Organizer: AIDS Vaccine 2009 Conference, 2009.10.19-22
  • Place of Presentation: Marriott Rive Gauche Conference Center, Paris, France
• [Presentation] 抗HIV-1V3抗体からの逃避過程で挿入されるV2領域の糖鎖が保存されるメカニズム-HIV-1の進化における耐性度と増殖能のバランスに関する考察- (2009)
  • Author(s): 畑田万紀子
  • Organizer: 第57回日本ウイルス学会学術集会
  • Place of Presentation: 都市センターホテル、東京
• [Presentation] 実験室HIV-1 R5株を用いた in vitro CCR5阻害薬(maraviroc)耐性ウイルス誘導の試み (2009)
  • Author(s): 石川哲也
  • Organizer: 第23回日本エイズ学会学術集会・総会
  • Place of Presentation: 名古屋国際会議場、名古屋
• [Presentation] 最近分離した7種の臨床HIV-1株を用いた in vitro ラルテグラビル耐性ウイルス誘導 (2009)
  • Author(s): 原田惠嘉
  • Organizer: 第23回日本エイズ学会学術集会・総会
  • Place of Presentation: 名古屋国際会議場、名古屋
• [Presentation] ケモカインレセプター阻害剤の臨床的研究～臨床分離株を用いたマラビロック耐性誘導～ (2009)
  • Author(s): 吉村和久
  • Organizer: 第23回日本エイズ学会学術集会・総会
  • Place of Presentation: 名古屋国際会議場、名古屋
• [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 (CROI 2009)
  • Place of Presentation: Montreal, Canada
• [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
  • Year and Date: 2008-11-28
• [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: Kumamoto
  • Year and Date: 2008-09-18
• [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.
  • Organizer: 9^<th> Kumamoto AIDS Seminar.
  • Place of Presentation: Kumamoto
  • Year and Date: 2008-09-18
• [Presentation] Different mutation in HIV-1 gp120 V3-tip regin for escape froma 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: Kumamoto
  • Year and Date: 2008-09-18
• [Presentation] 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)
  • Author(s): Narahara C., Yoshimura K., Hatada M., Harada S., Matsushita S.
  • Organizer: 9th Kumamoto AIDS Seminar
  • Place of Presentation: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
• [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: 9th Kumamoto AIDS Seminar
  • Place of Presentation: Aso Resort Grandvrio Hotel Kumamoto, Japan.
• [Presentation] In vitro induction of human immunodeficiency virus type 1 variants resistant to a low-molecular CD4 mimic compound. (2008)
  • Author(s): Yoshimura K., Hatada M., Harada S., Shibata J., Masuno H., Tamamura H., Matsushita S.
  • Organizer: 9th Kumamoto AIDS Seminar
  • Place of Presentation: Aso Resort Grandvrio Hotel, Kumamoto, Japan.
• [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
• [Remarks] ホームページ等
  • URL: http://yoshimura-project.p1.bindsite.jp/