Analysis of mechanism to induce potent neutralizing antibodies using SIV-infected macaques

• Project/Area Number: 18K06032
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 42040:Laboratory animal science-related
• Research Institution: Kumamoto University
• Principal Investigator: Kuwata Takeo 熊本大学, ヒトレトロウイルス学共同研究センター, 特定事業教員 (70346063)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 中和抗体 / SIV / 遺伝子多型 / アカゲザル / 抗体 / エイズ

Outline of Final Research Achievements

Analysis of induction of B404-class antibodies, which neutralize various SIV strains, was performed using 6 SIV-infected macaques. Induction of B404-class antibodies was associated with polymorphism of immunoglobulin Heavy chain gene, and macaques with the VH3.33 allele with E at 38th position and T at 65th position induced B404-class antibodies. The 38E was important for binding to Env and neutralizing activity. These results suggest that induction of neutralizing antibodies is determined by polymorphism of immunoglobulin genes.

Academic Significance and Societal Importance of the Research Achievements

近年、多様なHIV-1株を広範に中和するbnAbの誘導が効果的なワクチンの開発に重要であると考えられるようになった。また、特定のbnAbを誘導するための抗原の開発も進んでいる。しかしながら、HIV-1感染によるbnAbの誘導は稀であり、そのメカニズムも不明である。本研究では、SIV感染サル・モデルを用いて中和抗体誘導の解析を行い、中和抗体の誘導と抗体遺伝子の多型が密接に関連していることを示した。この結果は、今後のワクチン開発に遺伝子多型を考慮する必要があることをあきらかにした。

Research Products

• [Int'l Joint Research] NIH, NIAID(米国)
• [Journal Article] Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors (2021)
  • Author(s): Kobayakawa Takuya、Tsuji Kohei、Konno Kiju、Himeno Ai、Masuda Ami、Yang Tingting、Takahashi Kohei、Ishida Yusuke、Ohashi Nami、Kuwata Takeo、Matsumoto Kaho、Yoshimura Kazuhisa、Sakawaki Hiromi、Miura Tomoyuki、Harada Shigeyoshi、Matsushita Shuzo、Tamamura Hirokazu
  • Journal Title: Journal of Medicinal Chemistry Volume: 64 Issue: 3 Pages: 1481-1496
  • DOI: 10.1021/acs.jmedchem.0c01153
  • Peer Reviewed / Open Access
• [Journal Article] A Potent Anti-Simian Immunodeficiency Virus Neutralizing Antibody Induction Associated with a Germ Line Immunoglobulin Gene Polymorphism in Rhesus Macaques (2021)
  • Author(s): Matsuoka Saori、Kuwata Takeo、Ishii Hiroshi、Sekizuka Tsuyoshi、Kuroda Makoto、Sano Masato、Okazaki Midori、Yamamoto Hiroyuki、Shimizu Mikiko、Matsushita Shuzo、Seki Yohei、Saito Akatsuki、Sakawaki Hiromi、Hirsch Vanessa M.、Miura Tomoyuki、Akari Hirofumi、Matano Tetsuro
  • Journal Title: Journal of Virology Volume: 95 Issue: 7
  • DOI: 10.1128/jvi.02455-20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prediction of Contact Residues in Anti-HIV Neutralizing Antibody by Deep Learning (2020)
  • Author(s): Kaku Yu、Kuwata Takeo、Gorny Miroslaw K.、Matsushita Shuzo
  • Journal Title: Japanese Journal of Infectious Diseases Volume: 73 Issue: 3 Pages: 235-241
  • DOI: 10.7883/yoken.JJID.2019.496
  • NAID: 130007845455
  • ISSN: 1344-6304, 1884-2836
  • Year and Date: 2020-05-29
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Existence of replication-competent minor variants with different coreceptor usage in plasma from HIV-1-infected individuals (2020)
  • Author(s): Maeda Y, Takemura T, Chikata T, Kuwata T, Terasawa H, Fujimoto R, Kuse N, Akahoshi T, Murakoshi H, Van Tran G, Zhang Y, Pham CH, Pham AHQ, Monde K, Sawa T, Matsushita S, Nguyen TV, Van Nguyen K, Hasebe F, Yamashiro T, Takiguchi M.
  • Journal Title: Journal of Virology Volume: 94 Issue: 12
  • DOI: 10.1128/jvi.00193-20
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The role of conventional antibodies targeting the CD4 binding site and CD4-induced epitopes in the control of HIV-1 CRF01_AE viruses. (2019)
  • Author(s): Thida W, Kuwata T, Maeda Y, Yamashiro T, Tran GV, Nguyen KV, Takiguchi M, Gatanaga H, Tanaka K, Matsushita S
  • Journal Title: Biochem Biophys Res Commun Volume: 508 Issue: 1 Pages: 46-51
  • DOI: 10.1016/j.bbrc.2018.11.063
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synergistic inhibition of cell-to-cell HIV-1 infection by combinations of single chain variable fragments and fusion inhibitors (2019)
  • Author(s): Mamun MA, Kuwata T, Tanaka K, Alam M, Takahama S, Shimura K, Matsuoka M, Fukuda N, Morioka H, Tamamura H, Matsushita S
  • Journal Title: Biochemistry and biophysics reports Volume: 20 Pages: 100687-100687
  • Peer Reviewed
• [Journal Article] Total HIV-1 DNA dynamics and influencing factors in long-term ART-treated Japanese adults: a retrospective longitudinal analysis. (2018)
  • Author(s): Stanoeva KR, König A, Fukuda A, Kawanami Y, Kuwata T, Satou Y, Matsushita S.
  • Journal Title: J Acquir Immune Defic Syndr Volume: - Issue: 2 Pages: 239-247
  • DOI: 10.1097/qai.0000000000001662
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Polymorphism of Immunoglobulin germline gene restricts induction of bnAbs against SIV (2019)
  • Author(s): Kuwata T
  • Organizer: 第33回日本エイズ学会学術集会・総会
• [Presentation] Role of Conventional Antibodies in Control of HIV-1 CRF01_AE viruses (2018)
  • Author(s): Thida W, Kuwata T, Maeda Y, Tran G V, Nguyen K V, Takiguchi M, Gatanaga H and Matsushita S
  • Organizer: HIV Research for Prevention 2018
  • Int'l Joint Research
• [Presentation] 抗HIV治療薬ドルテグラビル、マラビロクを含むcART中に出現した耐性ウイルスの解析 (2018)
  • Author(s): 桑田岳夫、Kaung Htet Lin、蜂谷敦子、Win Thida、中田浩智、岩谷靖雅、吉村和久、松下修三
  • Organizer: 第28回抗ウイルス療法学会学術集会・総会
• [Presentation] Analysis of the envelope gene in the patient treated with maraviroc (2018)
  • Author(s): Lin K H, Kuwata T, Thida W, Shimizu M and Matsushita S
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] Synergistic inhibition by single chain fragment variables and fusion inhibitors in both cell-free and cell-associated HIV-1 infections (2018)
  • Author(s): Mamun M A, Maruta Y, Tanaka K, Alam M, Thida W, Takahama S, Kuwata T and Matsushita S
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Presentation] 抗イディオタイプ抗体による抗V3中和単クローン抗体産生B細胞単離方法の検討 (2018)
  • Author(s): 郭悠、桑田岳夫、田中和樹、Biswas Shashwata、Zahid MD Hassan、松下修三
  • Organizer: 第32回日本エイズ学会学術集会・総会
• [Patent(Industrial Property Rights)] 抗ＨＩＶ抗体の製造方法 (2018)
  • Inventor(s): 松下修三; 桑田岳夫; 清水 衛; 冨田正浩; 道下眞弘
  • Industrial Property Rights Holder: 松下修三; 桑田岳夫; 清水 衛; 冨田正浩; 道下眞弘
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-203114
  • Filing Date: 2018