Role of chemokine receptors in HIV infection and progression.

趋化因子受体在 HIV 感染和进展中的作用。

• 批准号: 09470125
• 负责人: NOJIMA Yoshihisa
• 金额: $ 7.23万
• 依托单位: GUNMA UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470125/
• 关键词: HIV; Chemokine receptor; Coreceptor; Tyrosine kinase; CCR3; CCR5; CXCR4

1. The role of CCR3 in HIV infection. C CR3, a receptor for chemokines such as eotaxin, has been recently identified as a coreceptor for certain types of HIV-1. Although CCR3 is strongly expressed on eosinophils in human peripheral blood cells, the expression on other cell types and its role in HIV infection have not been fully elucidated. In the current project, we have established monoclonal antibody against human CCR3. Using CCR3-expressing human glioma cells and CCR3-tropic HIV isolates, we found that this mAb specifically blocked HIV infection in vitro. Thus, this mAb provides a valuable probe in investigating the expression and function of HIV coreceptor, CCR3.2. Signal transduction pathways involving HIVenv-dependent cell fusion. Using HIVenv-dependent cell fusion system, we demonstrated that cytochalacin D and herbimycin but not pertussis toxin significantly inhibited HIV entry to cells. Moreover, confocal microscopy revealed colocalization of phosphotyrosyl proteins and F- act … More in in areas where cell membranes are about to fuse. These results suggest that protein tyrosine kin ase cascades and cytoskeletal reorganization play a critical role in HIVenv-dependent cell fusion. However, we found that HIVenv-dependent cell fusion could occur even in the absence of various non-receptor tyrosine kinases, including Src, Fyn, Lyn, FAK, or Abl, suggesting that these tyrosine kinases are not absolutely necessary for HIV-entry. However, redundancy commonly exists among these kinases. For example, we found that FAX-deficient cells expressed another FAK-family kinase, CAKbeta, which was considered to substitute the function of FAK.We also found that stimulation of human T cells with SDF1, a natural ligand for HTV coreceptor CXCR4, induced tyrosine phosphorylation of p105CasL.Since p105CasL is a signaling molecule involving in T cell receptor signal cascades, signals triggered by coreceptor engagement may play a role in abnormal function of T cells in HIV infected individuals. Less

1. CCR 3在HIV感染中的作用CCR 3是趋化因子如嗜酸性粒细胞趋化因子的受体，最近已被鉴定为某些类型的HIV-1的辅助受体。尽管CCR 3在人外周血细胞中的嗜酸性粒细胞上强烈表达，但在其他细胞类型上的表达及其在HIV感染中的作用尚未完全阐明。本研究建立了抗人CCR 3的单克隆抗体。使用表达CCR 3的人脑胶质瘤细胞和嗜CCR 3的HIV分离株，我们发现这种mAb在体外特异性阻断HIV感染。因此，该mAb为研究HIV辅助受体CCR3.2的表达和功能提供了有价值的探针。涉及HIV依赖性细胞融合的信号转导途径。利用HIVenv依赖的细胞融合系统，我们证明了细胞松弛素D和除莠霉素，而不是百日咳毒素显着抑制HIV进入细胞。此外，共聚焦显微镜显示磷酸酪氨酸蛋白和F-act共定位， ...更多信息 在细胞膜即将融合的区域。这些结果表明，蛋白酪氨酸激酶级联和细胞骨架重组在HIVenv依赖的细胞融合中起着关键作用。然而，我们发现，HIVenv依赖性细胞融合可以发生，即使在各种非受体酪氨酸激酶，包括Src，Fyn，林恩，FAK，或Abl的情况下，这表明这些酪氨酸激酶是不是绝对必要的HIV进入。然而，冗余通常存在于这些激酶之间。例如，我们发现FAX缺陷细胞表达另一种FAK家族激酶CAKbeta，它被认为可以替代FAK的功能。我们还发现，用HTV辅助受体CXCR 4的天然配体SDF 1刺激人类T细胞，会诱导p105 CasL的酪氨酸磷酸化。由于p105 CasL是参与T细胞受体信号级联的信号分子，由辅助受体结合触发的信号可能在HIV感染个体中T细胞的异常功能中起作用。少

项目成果

Ueki K et al: "Integrin-mediated signal trousduction in cells lacking focal adhesion kinase, p125^<FAK>" FEBS letters. 432. 197-201 (1998)

Ueki K 等人：“缺乏粘着斑激酶的细胞中整合素介导的信号传导，p125^<FAK>”FEBS 字母。

Ueki, K., Mimura, T., Nakamoto, T., Sasaki, T., Aizawa, S., Hirai, H., Yano, S., Naruse, T., and Nojima, Y.: "Integrin-mediated signal transduction in cells lacking focal adhesion kinase p125FAK." FEBS letters. 432. 197-201 (1998)

Ueki, K.、Mimura, T.、Nakamoto, T.、Sasaki, T.、Aizawa, S.、Hirai, H.、Yano, S.、Naruse, T. 和 Nojima, Y.：“整合素介导

Kanda H., Mimura T., Morino H., Hamasaki K,Nakamoto T,Hirai H., Morimoto C,Yazaki Y,and Nojima Y.: "Ligation of the T-cell antigen receptor induces tyrosine phosphorylation of p105CAasL,a member of p130Cas-related docking protein family, and its subsequen

Kanda H.、Mimura T.、Morino H.、Hamasaki K、Nakamoto T、Hirai H.、Morimoto C、Yazaki Y 和 Nojima Y.：“T 细胞抗原受体的连接诱导 p105CAasL 的酪氨酸磷酸化，成员

Kanda H et al: "Ligation of the c-cell antigen receptor induces tyrosine phosphorylation of p105(casl), a member of p130(cas-)-related dooking protein family, and its subsequent binding to Src hology-2 domain of c Crk" Eur.J.Immural. 27. 2113-2117 (1997)

Kanda H 等人：“c 细胞抗原受体的连接诱导 p105(casl)（p130(cas-) 相关 dooking 蛋白家族的成员）的酪氨酸磷酸化，及其随后与 c Crk 的 Src hology-2 结构域的结合

Kanda, H., Mimura, T., Hamasaki, K,Hirai, H., Yazaki, Y., and Nojima, Y.: "Fyn and Lck tyrosine kinases regulate tyrosine phosphorylation of p105CasL,a member of p130Cas docking protein family, in T-cell receptor-mediated signaling." Immunology. (in press

Kanda, H.、Mimura, T.、Hamasaki, K、Hirai, H.、Yazaki, Y. 和 Nojima, Y.：“Fyn 和 Lck 酪氨酸激酶调节 p105CasL（p130Cas 对接蛋白家族成员）的酪氨酸磷酸化，