エイズ制御のための基礎研究 柱3.エイズの予防・制御

• 研究課題/領域番号: 10180104
• 研究種目: 特定領域研究(A)
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 熊本大学
• 研究代表者: 松下 修三 熊本大学, エイズ学研究センター, 教授 (00199788)
• 研究分担者: 岩倉 洋一郎 東京大学, 医科学研究所, 教授 (10089120) ; 馬場 昌範 鹿児島大学, 医学部, 教授 (70181039) ; 満屋 裕明 熊本大学, 医学部, 教授 (20136724) ; 田中 勇悦 琉球大学, 医学部, 教授 (30163588) ; 藤井 信孝 京都大学, 薬学研究科, 教授 (60109014) ; 志田 壽利 北海道大学, 免疫科学研究所, 教授 (00144395) ; 高松 純樹 名古屋大学, 医学部附属病院, 助教授 (80221365)
• 研究期間 (年度): 1998 – 2001
• 研究課題ステータス: 完了 (2001年度)
• 配分額: 178,900千円 (直接経費: 178,900千円); 2001年度: 48,000千円 (直接経費: 48,000千円); 2000年度: 45,900千円 (直接経費: 45,900千円); 1999年度: 40,000千円 (直接経費: 40,000千円); 1998年度: 45,000千円 (直接経費: 45,000千円)
• キーワード: プロテアーゼ阻害剤 / CCR5阻害剤 / 薬剤耐性 / CXCR4阻害剤 / 膜融合阻害剤 / Vprトランスジェニックマウス / 中和抗体 / 逆転写酵素阻害剤 / HIV-1 / T140 / CXCR4拮抗剤 / トランスジェニックマウス / 遺伝子発現制御 / hu-PBL-SCIDマウス / ケモカインレセプター阻害剤 / 発症予防ワクチン / 抗ウイルス剤 / CTL / tat / 転写制御 / フィットネス / rev / u-CRM1

研究概要

満屋らは、新規CCR5阻害剤E913を開発し、AMD3100との併用でdual tropic virusに対して相乗効果を示すことを報告した。満屋らはまた、LD78βの構造活性相関を研究し、アミノ酸の置換により抗ウイルス活性が増強しうることを報告した。馬場らは、CCR5拮抗薬TAK-779に対する薬剤耐性ウイルスを誘導し、gp120領域の遺伝子変異を解析した結果、耐性獲得機序として、V3 loop領域のCCR5に対する親和性の増強を報告した。藤井らは強力且つ特異的CXCR4阻害剤、T140、およびHIV感染の動的分子機構を基盤に発見したgp41標的膜融合阻害剤SC34を探索子として、多剤耐性克服型抗HIV剤の創製研究(HIV entry/fusionに関わる分子認識・分子集合、ペプチド性薬物の生体内安定性向上等)を展開した。岩倉らは、Vprトランスジェニックマウスを作製したところ、末梢T細胞がアポトーシスを起こし1/20に減少したことから、VprがHIV感染のT細胞減少に関与している可能性を示した。このアポプトーシスにはFasは関与しておらず、BclxやBaxの関与が示唆された。田中らは、HIV-1非感染ヒト末梢血単核球と同一ドナーより培養して得られた成熟樹状細胞(不活化HIV-1で感作)をSCIDマウスに移植し、マウスにR5型HIV-1の感染に抵抗する因子を誘導した。この因子はヒトCD4+T細胞が産生するサイトカインで既知のβ-chemokine等とは異なる。松下らは、自己由来の分離株に対する中和抗体活性を検討し、19例中4例でHARRT開始後1年以上経過して中和活性の増加が認められたと報告した。またin vivoでの中和エスケープにはgp120の可変部ばかりでなくC3部分も関与することを示した。

研究成果

• [文献書誌] Kimura T.: "Reconstitution of spontaneous neutralizing antibody response against autologous human immunodeficiency virus during highly active antiretroviral therapy"J.Infect.Dis.. 185(1). 53-60 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Gatanada H.: "Amino acid substitutions in non-cleavage sites of the gag region are indispensable for high level HIV-1 resistance to protease inhibitors"J.Biol.Chem.. 277. 5952-5961 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Yasuda J.: "T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr"Virology. 285. 181-192 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tanaka R.: "A unique monoclonal antibody recognizing the third extracellular loop of the human CXCR4 induces lymphocytes agglutination and enhances HIV-1-mediated syncytium formation and productive infection"J.Virol.. 75. 11534-11543 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Baba M.: "A small-molecule nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity"Proc.Natl.Acad.Sci. USA. 96. 5698-5703 (1999)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Zhang WB: "A point mutation that confers constitutive activity to CXCR4 reveals T140 is an inverse gonist and AMD3100 and ALX4O-4C are weak partial agonists"J.Biol.Chem.. 277(27). 24515-24521 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Mitsuya H.: "The emergence of drug resistant HIV-1 variants and its impact on antiretroviral therapy of HIV-1 infection. In The Art of Antiretrovitral Therapy"American Society for Microbiology, Washington, D.C.. 33 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Kimura T. et al: "Reconstitution of spontaneous neutralizing antibody response against autologous human immunodeficiency virus during highly active antiretroviral therapy"J. Infect. Dis.. 185(1). 53-60 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Wang FX. et al: "Emergence of autologous neutralization-resistant variants from preexisting human immunodeficiency virus (HIV) quasi species during virus rebound in HIV type 1-infected patients undergoing highly active antiretroviral therapy"J. Infect. Dis.. 185(5). 608-617 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Gatanada H. et al: "Amino acid substitutions in non-cleavage sites of the gag region are indispensable for high level HIV-1 resistance to protease inhibitors"J. Biol. Chem.. 277. 5952-5961 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Miyakawa T. et al: "Identification of amino acid residues critical for LD78β (a variant of human macrophage inflammatory protein-1 α) binding to CCR5 and inhibition of R5 HIV-1 replication"J. Biol. Chem.. 277. 4649-4655 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Yasuda J. et al: "T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr"Virology. 285. 181-192 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tanaka R. et al: "A unique monoclonal antibody recognizing the third extracellular loop of the human CXCR4 induces lymphocytes agglutination and enhances HIV-1-mediated syncytium formation and productive infection"J. Virol.. 75. 11534-11543 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Zhang WB. et al: "A point mutation that confers constitutive activity to CXCR4 reveals T140 is an inverse gonist and AMDS3100 and ALX40-4C are weak partial agonists"J. Biol. Chem.. 277. 24515-24521 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Wang FX: "Emergence of Autologous Neutralization-Resistant Variants from Preexisting Human Immunodeficlency Virus (HIV) Quasi Species during Virus Rebound In HIV Type 1-Infected Patients Undergoing Highly Active Antiretroviral Therapy"J Infect Dis. 185. 608-617 (2002)
• [文献書誌] Kimura T: "Reconstitution of Spontaneous Neutralizing Antibody Response against Autologous Human Immunodeficiency Virus during Highly Active Antiretroviral Therapy"J Infect Dis. 185. 53-60 (2002)
• [文献書誌] Ikegawa M: "Elevated plasma SDF-1 protein level in the progression of HIV-1 infection/AIDS"AIDS Res. Hum. Retrov. 17. 587-595 (2001)
• [文献書誌] Murakami T: "Parkinsonian symptoms as an initial manifestation in a Japanese patient with acquired immunodeficiency syndrome and toxoplasma infection"Internal Medicine. 39. 1111-1114 (2000)
• [文献書誌] Matsushita S: "Current status and future issues in the treatment of HIV-1 infection"Int J Hematol. 72. 20-27 (2000)
• [文献書誌] Tugarinov V: "NMR structure of an anti gp-120 antibody complex with a V3-peptide reveals a surface important for co-receptor binding"Structure. 8. 385-395 (2000)
• [文献書誌] Suzuki, S.: "Diverse transcriptional response of CD4(+) T cells to stromal cell-derived factor (SDF)-1 ; cell survival promotion and priming effects of SDF-1 on CD4(+) T cells"J. Immunol.. 167. 3064-3073 (2001)
• [文献書誌] Maeda, K.: "Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5"J Biol Chem. 276. 35194-35200 (2001)
• [文献書誌] Kodama, E: "4'-Ethynyl nucleoside analogs : potent inhibitors active against multi-drug-resistant HIV variants in vitro"Antimicrob. Agents Chemother.. 45. 1539-1546 (2001)
• [文献書誌] Miyakawa, T.: "Identification of amino acid residues critical for LD78β(a variant of human macrophage inflammatory protein-1α) binding to CCR5 and inhibition of R5 HIV-1 replication"J. Biol. Chem.. 277. 4649-4655 (2002)
• [文献書誌] Gatanaga, H.: "Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV 1 resistance against protease inhibitors"J Biol Chem. 277. 5952-5961 (2002)
• [文献書誌] Yoshimura, K.: "A Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor, UIC-94003(TMC-126),and Selection of a Novel(A28S) Mutation in the Protease Active Site"J Virol. 76. 1394-1358 (2002)
• [文献書誌] Okamoto M: "Suppression of cytokine production and neural cell death by the anti-inflammatory alkaloid cepharanthine : a potential agent against HIV-1 encephalopathy"Biochem. Pharmacol.. 62. 747-753 (2001)
• [文献書誌] Nitanda T: "Three-drug combinations of emivirine and nucleoside reverse transcriptase inhibitors in vitro : Long-term culture of HIV-1-infected cells and breakthrough viruses"Antiviral Chem. Chemother.. 12. 161-167 (2001)
• [文献書誌] Takashima K: "Inhibitory effects of small-molecule CCR5 antagonists on human immunodeficiency virus type 1 envelope-mediated membrane fusion and viral replication"Antimicrob. Agents Chemother. 45. 3538-3543 (2001)
• [文献書誌] Baba M: "Anti-HIV-1 activity and structure-activity relationship of cepharanoline derivatives in chronically infected cells"Antimicrob. Agents Chemother. 12. 307-312 (2001)
• [文献書誌] Takeda, K: "Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells"Nature Medicine. 7. 94-100 (2001)
• [文献書誌] Seino, K: "Requirement for NKT cells in the induction of allograft tolerance"Proc. Natl. Acad. Sci. U.S.A. 98. 2577-2581 (2001)
• [文献書誌] Nakae, S: "IL-1 enhances T cell-dependent antibody production through induction of CD4OL and OX40 on T cells"J. Immunol.. 167. 90-97 (2001)
• [文献書誌] Yasuda, J: "T cell apoptosis causes peripheral T cell depletion in mice transgenic for the HIV-1 vpr"Virology. 285. 181-192 (2001)
• [文献書誌] Yokoyama, H.: "Pathological changes of renal epithelial cells in mice transgenic for the TT virus ORF1 gene"J. Gen. Virol.. 83. 141-150 (2002)
• [文献書誌] Saijo, S.: "Suppression of autoimmune arthritis in IL-1-deficient mice in which T cell activation is impaired due to low levels of CD4OL and 0X40 expression on T cells"Arth.. 46. 533-544 (2002)
• [文献書誌] Tanaka R: "A unique monoclonal antibody recognizing the third extracelluar loop of the human CXCR4 Induces lymphocyte agglutination and enhances human Immunodeficlency virus type-1-mediated syncytium formation and productive Infection"J. Virol. 75. 11534-11543 (2001)
• [文献書誌] Baba E: "Functional CD4 T cells after intercellular molecular transfer of OX40 ligand"J. Immunol. 167. 875-883 (2001)
• [文献書誌] Takahashi Y: "OX40 stimulation by gp34/0X40 ligand enhancee productive HIV-1 infection"J. Virol. 75. 6748-6757 (2001)
• [文献書誌] Hanon E: "High production of interferon gamma but not interleukin-2 by human T-lymphotropic virus type-I-infected peripheral blood mononuclear cells"Blood. 98. 721-726 (2001)
• [文献書誌] Shioda T: "Naturally occurring deletional mutation in the C-terminal cytoplasmic tail of CCR5 affects surface trafficking of CCR5"J. Virol. 75. 3462-3468 (2001)
• [文献書誌] Kavlick, M.F., Mitsuya, H.: "The emergence of drug resistant HIV-1 variants and its impact on antiretroviral therapy of HIV-1 infection. In "The Art of Antiretroviral Therapy" (Ed. Erik De Clercq)"American Society for Microbiology, Washington, D.C.. 33 (2001)
• [文献書誌] Baba M: "Cellular factors as targets for anti-human immunodeficiency virus therapy In : De Clercq E(Ed), Antiviral Therapy"ASM Press, Wasgington, DC. 26 (2001)
• [文献書誌] Maeda,Y.: "Involvement of both V2 and V3 region of CCR5-tropic human immunodeficiency virus type-1 envelope for reduced sensitivity to macrophage inflammatory protein α."J.Virol.. 74. 1787-1793 (2000)
• [文献書誌] Matsushita,S.: "Current status and future issues in the treatment of HIV infection."Int.J.Hematol.. (in press). (2000)
• [文献書誌] Tugarinov,V.: "NMR structure of an anti gp-120 antibody complex with a V3-peptide reveals a surface important for co-receptor binding."Structure. 8. 385-395 (2000)
• [文献書誌] Murakami,T.: "Parkinsonian symptoms as an initial manifestation in a Japanese patient with acuired immunodeficinecy syndrome and toxopolasma infection"Internal Medicine. 39. 1111-1114 (2000)
• [文献書誌] Ikegawa,M.: "Elevated plasma SDF-1 protein level in the progression of HIV-1 infection/AIDS."AIDS Res.Hum.Retrov.. (in press).
• [文献書誌] Falloon,J.: "Combination therapy with amprenavir, abacavir, and efavirenz in human immunodeficiency virus (HIV)-infected patients failing a protease-inhibitor regimen : pharmacokinetic drug interactions and antiviral activity."Clin.Infect.Dis.. 30. 313-318 (2000)
• [文献書誌] Ohrui,H.: "Syntheses of 4'-C-Ethynyl-beta-D-arabino-and 4'-C-Ethynyl-2'deoxy-beta-D-ribo-pentofuranosylpyrimidines and -purines and Evaluation of Their Anti-HIV Activity."J Med Chem.. 43. 4516-4525 (2000)
• [文献書誌] Sei,S.: "Identification of a key target sequence to block human immunodeficiency virus type 1 replication within the gag-pol transframe domain."J Virol.. 74. 4621-4633 (2000)
• [文献書誌] Baba,M.: "Establishment of a CCR5-expressing T-lymphoblastoid cell line highly susceptible to R5 HIV-1"AIDS Res.Hum.Retrovir.. 16. 935-941 (2000)
• [文献書誌] Shiraishi,M.: "Discovery of novel, potent and selective small molecule CCR5 antagonists as anti-HIV-1 agents : synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety."J.Med.Chem.. 43. 2049-2063 (2000)
• [文献書誌] Tanaka,J.: "Lipopolysaccharide-induced HIV-1 expression in transgenic mice is mediated by tumor necrosis factor-a and interleukin-1, but not by interferon-g nor interleukin-6."AIDS. 14. 1299-1307 (2000)
• [文献書誌] Horai,R.: "Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in IL-1 receptor antagonist-deficient mice."J.Exp.Med.. 191. 313-320 (2000)
• [文献書誌] Hayakawa,Y.: "Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells."Nature Medicine. 7. 94-100 (2001)
• [文献書誌] Kanbara,K.: "A Study of Anti-HIV Compounds Which Interfere the Virus Entry via Coreceptor CXCR4"Kanssenshogaku Zasshi. 74. 237-244 (2000)
• [文献書誌] Ponomaryov,T.: "Induction of the Chemokine Stromal-derived Factor-1 Following DNA Damage Improves Human Stem Cell Function."J.Clin.Invest.. 106. 1331-1339 (2000)
• [文献書誌] Tamamura,H.: "Pharmacophore Identification of a Specific CXCR4 Inhibitor, T140, Leads to Development of Effective Anti-HIV Agents with Very High Selectivity Indexes"Bioorg.Med.Chem.Lett.. 10. 2633-2637 (2000)
• [文献書誌] Tamamura,H.: "Conformational Study of a Highly Specific CXCR4 Inhibitor, T140, Disclosing the Close Proximity of Its Intrinsic Pharmacophores Associated with Strong Anti-HIV Activity"Bioorg.Med.Chem.Lett.. 11. 359-362 (2001)
• [文献書誌] Miura,Y.: "Critical contribution of TNF-related apoptosis-inducing ligand (TRAIL) to apoptosis of CD4+ T cells in HIV-1-infected hu-PBL-SCID mice."J.Exp.Med.. (in press).
• [文献書誌] Baba,M.: "Cellular factors as targets for anti-human immunodeficiency virus therapy."De Clercq E (Ed), Antiviral Therapy, ASM Press, Wasgington, DC.(in press). (2001)
• [文献書誌] Y.Maeda: "Involvement of both V2 and V3 region of CCR5-tropic human immunodeficiency virus type-1 envelope for reduced sensitivity to macrophage inflammatory protein α"J.Virol.. 74. 1787-1793 (2000)
• [文献書誌] S.Matsushita: "Current status and future issues in the treatment of HIV infection"Int.J.Hematol.. (in press). (2000)
• [文献書誌] Tugarinov V: "NMR structure of an anti gp-120 antibody complex with a V3-peptide reveals a surface important for co-receptor binding"Structure. (in press). (2000)
• [文献書誌] P.Kosalaraksa: "Comparative fitness of multi-didoexynucleoside-resistant(MDR)-HIV-1 in an in vitro competitive HIV-1 replication assay(CHRA)"J.Viol. 73. 5356-5363 (1999)
• [文献書誌] K.Yoshimura: "JE-2147:a novel dipeptide protease inhibitor(PI) that potently inhibits multi-PI resistant HIV-1"Proc.Natl.Acad.Sci USA. 96. 8675-8680 (1999)
• [文献書誌] K.Ibuki: "Protective effects to simian immunodeficiency virus agm(SIVagm) infection in cynomolgus monkeys immunized with a recombinant vaccinia virus expressing the SIVagm envelop gene"Vaccine. 18. 511-516 (1999)
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