REGULATION OF HIV-MEDIATED CD4 T CELL APOPTOSIS

描述：确定HIV导致 CD 4和CD 8 T细胞的耗竭是难以实现的。多个 机制已经被假定，一般分为两大类; 直接杀死HIV感染细胞或间接杀死未感染的HIV T细胞通过HIV依赖机制。HIV的包膜（env）可以介导死亡 受感染和未受感染的T细胞。趋化因子受体的发现 作为艾滋病毒的共同受体， 在介导env引发的T细胞死亡中的作用。一些初步数据已经 获得的结果表明，R5和X4 HIV及其相应的受体 T细胞死亡通过不同的分子机制。R5 env导致Fas-和 未感染的CD 4 T细胞的半胱天冬酶依赖性死亡。相反，X4 env 不仅未感染的CD 4，而且CD 8， T细胞，以及HIV感染的CD 4 T细胞。这促使我们 假设env可以介导未感染和HIV感染T细胞死亡 细胞（包括CD 8 T细胞）和介导这种细胞的分子机制 死亡最终取决于由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X4 env导致细胞死亡的信号转导途径 未感染的CD 4和CD 8 T细胞通过CXCR 4。二）确定R5 env如何 与CD 4和CCR-的相互作用导致Fas依赖性凋亡。III）文件 env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的相互作用，并翻译这种 对艾滋病毒感染患者淋巴组织的发现。识别 CCR-和CXCR 4介导T细胞增殖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及其意义 也可以扩增到已知在免疫过程中靶向的其他非CD 4 T细胞。 HIV感染过程中表达趋化因子受体，如神经元， 上皮细胞和NK细胞。

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.