REGULATION OF HIV-MEDIATED CD4 T CELL APOPTOSIS

HIV 介导的 CD4 T 细胞凋亡的调节

• 批准号: 6312530
• 负责人: CARLOS V PAYA
• 金额: $ 31.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6312530
• 关键词: CD95 molecule; HIV envelope protein; HIV infections; apoptosis; biological signal transduction; clinical research; cytokine receptors; cytotoxic T lymphocyte; helper T lymphocyte; human subject; pathologic process; second messengers; tissue /cell culture

DESCRIPTION: Identification of the mechanism(s) through which HIV leads to depletion of both CD4 and CD8 T cells has been elusive. A multitude of mechanisms have been postulated, generally falling into two broad categories; direct killing of the HIV infected cell or indirect death of HIV of uninfected T cells by HIV dependent mechanisms. The envelope of HIV(env) can mediate death of both infected and uninfected T cells. The discovery of chemokine receptors as HIV co-receptors has provided the opportunity to study their potential role in mediating env-triggered T cell death. A number of preliminary data have been obtained indicating that R5 and X4HIV, and their corresponding receptors exert T cell death through distinct molecular mechanisms. R5env leads to a Fas- and caspase-dependent death of uninfected CD4 T cells. On the contrary, X4env leads to a Fas- and caspase-independent death of not only uninfected CD4 but also CD8 T cells, as well as HIV infected CD4 T cells. This has prompted us to hypothesize that env can mediate death of both uninfected and HIV infected T cells (including CD8 T cells) and that the molecular mechanism mediating such death is ultimately dependent on the type of chemokine receptor engaged by env. To address this hypothesis we propose the following three specific aims I) Study the signal transduction pathways whereby X4env leads to the death of uninfected CD4 and CD8 T cells via CXCR4. II) Determine how the R5env interaction with CD4 and CCR- leads to Fas dependent apoptosis. III) Document the necessary role of env in mediating killing of HIV infected T cells through its interaction with the corresponding chemokine receptor and translate such findings to lymphoid tissue from HIV infected patients. Identification of the molecular mechanisms and second messengers whereby CCR- and CXCR4 mediate T cell death will help in determining how HIV infection ultimately ravages the immune system. The implications derived from chemokine receptor mediated death can also be expanded to other non CD4 T cells known to be targeted during the course of HIV infection and to express chemokine receptors such as neurons, epithelial cells, and NK cells.

描述：艾滋病病毒导致人类免疫缺陷的机制的确定(S) CD4和CD8T细胞的枯竭一直难以捉摸。一大批 机制一直被假定，大体分为两大类； 直接杀死感染艾滋病毒的细胞或间接杀死未感染的艾滋病毒 T细胞通过HIV依赖机制。HIV包膜(Env)可介导死亡 感染和未感染的T细胞。趋化因子受体的发现 因为艾滋病毒共受体为研究它们的潜在作用提供了机会 在介导包膜病毒引发的T细胞死亡中起作用。一些初步数据已经公布 表明R5和X4HIV及其相应的受体发挥作用 T细胞通过不同的分子机制死亡。R5env通向Fas-和 未感染的CD4T细胞依赖caspase的死亡。相反，X4env领先 不依赖于Fas和caspase的未感染的CD4和CD8的死亡 T细胞，以及HIV感染的CD4T细胞。这促使我们 假设环境病毒可以调节未感染和感染HIV的T细胞的死亡 细胞(包括CD8 T细胞)及其介导的分子机制 死亡最终取决于env参与的趋化因子受体的类型。 为了解决这一假设，我们提出了以下三个具体目标： 研究X4env导致细胞死亡的信号转导途径 通过CXCR4未感染的CD4和CD8 T细胞。Ii)确定R5env如何 与CD4和Ccr-的相互作用导致Fas依赖性的细胞凋亡。三)文件 包膜蛋白在介导HIV感染的T细胞杀伤中的必要作用 它与相应的趋化因子受体相互作用并翻译这样的 HIV感染者淋巴组织的检测结果。身份识别 CCR-和CXCR4介导T细胞死亡的分子机制和第二信使 细胞死亡将有助于确定艾滋病毒感染最终如何破坏 免疫系统。趋化因子受体介导的死亡的意义 也可以扩增到其他已知的非CD4T细胞在 并表达趋化因子受体，如神经元， 上皮细胞和NK细胞。