エイズ制御のための基礎研究 柱1.HIVの複製における宿主因子

• 研究課題/領域番号: 10180101
• 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: 東北大学 (2000-2001); 東京大学 (1998-1999)
• 研究代表者: 小柳 義夫 (2000-2001) 東北大学, 医学系研究科, 教授 (80215417); 永井 美之 (1998-1999) 東京大学, 医科学研究所, 教授 (20022874)
• 研究分担者: 増田 貴夫 東京医科歯科大学, 医歯学総合研究科, 助教授 (80219336) ; 岡本 尚 名古屋市立大学, 医学部, 教授 (40146600) ; 塩田 達雄 大阪大学, 微生物病研究所, 教授 (00187329) ; 志田 壽利 北海道大学, 遺伝子病制御研究所, 教授 (00144395) ; 足立 昭夫 徳島大学, 医学部, 教授 (90127043) ; 高橋 秀宗 国立感染症研究所, 主任研究員 (70260271) ; 生田 和良 大阪大学, 微生物病研究所, 教授 (60127181)
• 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: 185,100千円 (直接経費: 185,100千円); 2001年度: 45,100千円 (直接経費: 45,100千円); 2000年度: 42,800千円 (直接経費: 42,800千円); 1999年度: 45,000千円 (直接経費: 45,000千円); 1998年度: 52,200千円 (直接経費: 52,200千円)
• キーワード: HIV / エイズ / CD4陽性T細胞 / NF-κB / ケモカインレセプター / レトロウイルス / インテグレーション / 核外移行 / ゲノム / TAT / インテグレース / REV / 核内因子 / HIV-1 / gp41 / Nef / 阻害剤 / RANTES / サル細胞 / SIV / SDFA / CD26 / 糖鎖 / 逆転写 / アクセサリー蛋白 / サブタイプEゲノム

研究概要

小柳はウイルス感染個体内でCD4陽性T細胞がアポトーシスに陥るのに関わる細胞性因子であるアポトーシス誘導シグナルとしてFasLでなくTRAILが関与することをSCIDマウスにヒト細胞を移植した感染系を用いて明らかにした。さらに神経組織にウイルスが侵入すると同じTRAILが中枢神経細胞を殺すことを見出した。塩田はウイルスのコレセプターであるCCR5にアジア人特有の遺伝子変異をみつけ、この変異によりこの分子の細胞表面への輸送が低下しHIVに対する感受性が低下することを見つけた。さらにIL-4の遺伝子変異が起こるとエイズ発症が遅延することも見出した。岡本はHIVの転写に必須の細胞性因子としてNF-κB p65のトランス活性化領域に結合してコレプレッサーとして働くAES/TLEとコアクチベーターとして働くFUS/TLSを発見し、ウイルス発現調節機構の新たなメカニズムを明らかにした。増田はHIVインテグレースの細胞核内への移行シグナル部位が従来考えられていたものと異なることを見つけ、この分子移行に関与する細胞性因子の同定を目指している。志田はウイルスRNAの核内から核外へ移行に必須であるウイルス蛋白質Revに結合するCRM1の機能ドメインを明らかにし、Revの多量体化にCRAM1が必要であること、さらにマウス細胞内でも機能を発揮することを見つけ、マウス細胞へのヒトCRAM1遺伝子の導入は意義のあることがわかった。

研究成果

• [文献書誌] Ichiyama K.: "A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636,exhibits a potent and selective anti-HIV-1 activity"Proc.Natl.Acad.Sci. USA. 100(7). 4185-4190 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Miura Y.: "Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in a murine model of HIV central nervous system infection"Proc.Natl.Acad.Sci. USA. 100(5). 2777-2782 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Tsurutani N.: "Identification of Critical Amino Acid Residues in HIV-1 IN Required for Efficient Proviral DNA Formation at Steps Prior to Integration in Dividing and Non-dividing Cells"J.Virol.. 74. 4795-4806 (2000)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Hakata Y.: "The Carboxy-termina 1 Region of the Human Immunodeficiency Virus-1 Protein Rev has Multiple Roles in Mediating CRM1-related Rev Functions"J.Virol.. 76(16). 8079-8089 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Uranishi H.: "Involvement of the pro-oncoprotein TLS (Translocated in liposarcoma) in nuclear facto-κB p65-mediated transcription as a coactivator"J.Biol.Chem.. 276. 13395-13401 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Okamoto T.: "Methods in Enzymology"Academic Press, Inc.. 50 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] Ichiyama K. et al: "A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity"Proc. Natl. Acad. Sci. USA. 100(7). 4185-4190 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Miura Y. et al: "Tumor necrosis factor-related apoptosis-inducing ligand induces neuronal death in a marine model of HIV central nervous system infection"Proc. Natl. Acad. Sci. USA. 100(5). 2777-2782 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Shioda T. et al: "Naturally occurring deletional mutation in the C-terminal cytoplasmic tail of CCR5 affects surface trafficking of CCR5"J. Virol.. 75. 3462-3468 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Tsurutani N. et al: "Identification of Critical Amino Acid Residues in HIV-1 IN Required for Efficient Proviral DNA Formation at Steps Prior to Integration in Dividing and Non-dividing Cells.system infection"J. Virol.. 74. 4795-4806 (2000)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] Hakata Y. et al: "The Carboxy-termina 1 Region of the Human Immunodeficiency Virus-1 Protein Rev has Multiple Roles in Mediating CRM1-related Rev Functions"J. Virol. 76(16). 8079-8089 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
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  • 説明: 「研究成果報告書概要(欧文)」より
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