APOPTOSIS AND AIDS--ROLE OF TAT GENE

工作总结：提出了一些机制来解释 HIV感染者辅助性CD 4+细胞的耗竭。 这 损失可能与增加的凋亡有关。 我们目前的研究 实验室的目的是了解所采用的机制， 细胞程序性死亡。 我们着重于以下方面的作用： 艾滋病毒达特基因在这个过程中。 达特可以调节的氧化还原状态 通过改变各种酶的活性来改变细胞的 向促氧化剂状态发展。 我们已经证明， 氧化还原状态可导致细胞通过凋亡而死亡。 目前我们正在 研究细胞死亡的调控， 达特和TNF-α 我们已经产生了几个细胞系， 组成性激活的达特。在这些细胞中，达特增强TNF诱导的 转录因子NF-κ-B的激活， 细胞毒 此外，我们已经表明，TNF诱导的毒性是 由TNFRI介导。 此外，我们还表明， 重组可溶性HIV达特蛋白可诱导TNFRI表达。通过 增加TNFRI，达特能够增强TNF的作用。 这些 影响最有可能导致局部稳态的变化， 有助于艾滋病的发展。

Summary of Work: A number of mechanisms have been proposed to explain the depletion of helper CD4+ cells in HIV-infected individuals. This loss may be associated with increase apoptosis. Current studies in our laboratory are directed toward understanding the mechanisms employed by cells undergoing programmed cell death. We have focused on the role of the HIV tat gene in this process. Tat can modulate the redox state of cells by altering the activity of various enzymes to shift the cellular state toward pro-oxidant conditions. We have shown that the altered redox state can cause cells to die by apoptosis. Currently we are studying the regulation of the cell death mediated by the interactions of the tat and TNF-alpha. We have generated several cell lines that contain constitutively activated tat. In these cells, tat potentiated TNF-induced activation of the transcription factor, NF-kappa-B, and cellular cytotoxicity. In addition we have shown that TNF-induced toxicity is mediated by the TNFRI. Furthermore, we have shown that addition of recombinant, soluble HIV tat protein could induce TNFRI expression. By increasing TNFRI, tat is able to potentiate the effects of TNF. These effects most likely lead to changes of local homeostasis and may contribute to the AIDS disease development.