2000 年度実績報告書

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

研究課題/領域番号	10180104
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, 大学院・薬学研究科, 教授 (60109014)
キーワード	HIV-1 / 薬剤耐性 / CCR5阻害剤 / 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
研究概要	本研究班では4つのアプローチからエイズの予防・制御を目指した基礎研究を行っている。すなわち、1)HIVの生活環の各ステップに作用する新規抗ウイルス剤の開発、2)薬剤耐性の機序とその克服、3)HIV感染個体の宿主因子の解明及びそれに基づいた治療法の開発、4)小動物モデルを用いた病態の解析と治療法の開発である。本年度の実績として、満屋らは0.3nMという低濃度で有効でしかも交叉耐性のない新規プロテアーゼ阻害剤UIC94003を開発した。ケモカインレセプターを標的とした治療薬として藤井らはCXCR4拮抗剤T140の立体構造を基に、安定性を向上した高活性・低細胞毒性抗HIV剤を見いだした。また馬場らはCCR5阻害剤の作用機構を解明するため,R5HIV-1に強い感受性を有する培養細胞株MOLT-4/CCR5細胞を樹立し,TAK-779存在下におけるウイルスの長期培養実験にて耐性ウイルスを得ることに成功した。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、まれながら治療経過中に中和抗体が出現してくる症例があることを示した。動物モデルとして岩倉らはHIV遺伝子導入マウスの検索からHIV-1の発現誘導が細胞周期依存性に起こること、CyclinT1によりマウスでのHIVの発現効率が格段に向上することを示した。田中らはSCIDマウス脾臓内にヒトPBMCとHIV-1パルス樹状細胞を移植し、HIV-1感染免疫応答を誘導することに成功した。このようにエイズ制御に向けて可能性のある新規薬剤の臨床応用を意識した基礎研究が進んでいる。さらに動物モデルや感染個体の研究から新しい予防・制御の方法についての手がかりが得られている。

研究成果
(19件)

すべてその他

すべて文献書誌 (19件)

[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)

2000 年度 実績報告書

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)

研究成果

[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)

2000 年度実績報告書

エイズ制御のための基礎研究柱3.エイズの予防制御

松下修三熊本大学, エイズ学研究センター, 教授 (00199788)