Basic Research for AIDS control A03 ; Prevention and control of AIDS

艾滋病控制基础研究A03；

• 批准号: 10180104
• 负责人: MATSUSHITA Shuzo
• 金额: $ 114.5万
• 依托单位: KUMAMOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas (A)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10180104/
• 关键词: Protease inhibitor; CCR5 inhibitor; Drug resistance; CXCR4 inhibitor; Membrane fusion inhibitor; Vpr transgenic mouse; Neutralizing antibody; Reverse transcriptase inhibitor; 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

Mitsuya had developed a novel CCR5 inhibitor, E913, and shown that the combination of this drug with AMD3100 suppressed the replication of dual tropic virus synergistically. Mitsuya also analyzed the structural biology of LD78β and reported that the replacement of certain amino acid facilitated the anti-viral activity of this chemokine. Baba isolated a virus clone resistant to CCR5 antagonist, TAK-779, analyzed mutations in the gp120 gene of this clone, and found that mutations in V3 region facilitated the affinity of gp120 to CCR5, resulting in the resistance to TAK-779. Fujii developed a potent and selective inhibitor for CXCR4, T140, and a membrane fusion inhibitor, SC34, and analyzed the drug resistance using SC34 as a molecular probe. Iwakura established a Vpr transgenic mouse and showed that peripheral T cells decreased in number by 1/20 in this mouse, suggesting that Vpr might be involved in the depletion of peripheral T cells. Tanaka reported that immunized SCID-PBL mice with dendritic cells from the same donor pulsed with inactivated HIV-1 showed the resistance to R5 HIV-1 challenge, Matsushita analyzed the activity of neutralizing antibodies in infected patients, and found that 4 cases among 19 patients showed the upregulation of neutralizing activities more than 1 year after introduction of HAART. He also reported that virus escape from neutralizing antibody in vivo was associated with the mutations in the C3 region as well as the variable regions of gp120.

Mitsuya开发了一种新的CCR 5抑制剂E913，并显示该药物与AMD 3100的组合协同抑制双嗜性病毒的复制。Mitsuya还分析了LD 78 β的结构生物学，并报道了某些氨基酸的替换促进了这种趋化因子的抗病毒活性。Baba分离到一个对CCR 5拮抗剂TAK-779耐药的病毒克隆，分析了该克隆gp 120基因的突变，发现V3区的突变促进了gp 120与CCR 5的亲和力，导致对TAK-779耐药。Fujii开发了一种有效的选择性CXCR 4抑制剂T140和一种膜融合抑制剂SC 34，并使用SC 34作为分子探针分析了耐药性。Iwakura建立了Vpr转基因小鼠，并显示该小鼠的外周T细胞数量减少了1/20，这表明Vpr可能参与了外周T细胞的耗竭。Tanaka报道用来自同一供体的树突状细胞免疫的SCID-PBL小鼠显示出对R5 HIV-1攻击的抵抗力，Matsushita分析了感染患者的中和抗体活性，发现19例患者中有4例在引入HAART后1年以上显示中和活性上调。他还报道了病毒在体内从中和抗体逃逸与C3区以及gp 120可变区的突变有关。

项目成果

J.Wang: "IL-4 and a glucocorticoid up-regulate CXCR4 expression on human CD4+T lymphocytes and enhance HIV-1 replication"J.of Leukocyte Biology.. 64. 642-649 (1998)

J.Wang：“IL-4 和糖皮质激素上调人 CD4 T 淋巴细胞上的 CXCR4 表达并增强 HIV-1 复制”J.of Leukcyto Biology.. 64. 642-649 (1998)

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)

Sei,S.：“鉴定阻止人类免疫缺陷病毒 1 型在 gag-pol 转架结构域内复制的关键靶序列。”J Virol.. 74. 4621-4633 (2000)

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)

Baba M.：“一种小分子非肽 CCR5 拮抗剂，具有高效且选择性的抗 HIV-1 活性”Proc.Natl.Acad.Sci。

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)

Mitsuya H.：“耐药 HIV-1 变体的出现及其对 HIV-1 感染的抗逆转录病毒治疗的影响。抗逆转录病毒治疗的艺术”美国微生物学会，华盛顿特区。33 (2001)

Kanbara,K.: "A Study of Anti-HIV Compounds Which Interfere the Virus Entry via Coreceptor CXCR4"Kanssenshogaku Zasshi. 74. 237-244 (2000)

Kanbara,K.：“通过辅助受体 CXCR4 干扰病毒进入的抗 HIV 化合物的研究”Kanssenshogaku Zasshi。