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：识别 HIV 导致的机制 CD4 和 CD8 T 细胞的耗竭一直难以捉摸。众多的 机制已被假设，一般分为两大类； 直接杀死HIV感染细胞或间接杀死未感染HIV的细胞 T 细胞通过 HIV 依赖性机制。 HIV（env）的包膜可以介导死亡 感染和未感染的 T 细胞。趋化因子受体的发现 因为 HIV 共同受体提供了研究其潜在作用的机会 介导环境触发的 T 细胞死亡。已有多项初步数据 获得表明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 导致 Fas- 和 未感染 CD4 T 细胞的 caspase 依赖性死亡。相反，X4env 领先 不仅导致未感染的 CD4 甚至 CD8 发生不依赖 Fas 和 caspase 的死亡 T 细胞，以及 HIV 感染的 CD4 T 细胞。这促使我们 假设 env 可以介导未感染和 HIV 感染 T 的死亡 细胞（包括 CD8 T 细胞）以及介导这种作用的分子机制 死亡最终取决于 env 参与的趋化因子受体的类型。 为了解决这个假设，我们提出以下三个具体目标 I) 研究X4env导致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 依赖性细胞凋亡。三）文件 env 在介导杀死 HIV 感染的 T 细胞中的必要作用 它与相应的趋化因子受体相互作用并翻译这种 对艾滋病毒感染者的淋巴组织的研究结果。鉴定 CCR-和CXCR4介导T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影响 也可以扩展到已知的其他非 CD4 T 细胞 HIV 感染过程并表达趋化因子受体，例如神经元， 上皮细胞和NK细胞。