APOPTOSIS AND AIDS--ROLE OF TAT GENE

已经提出了许多机制来解释HIV感染个体中辅助性CD 4+细胞的耗竭。这种损失可能与细胞凋亡增加有关。我们实验室目前的研究是针对理解细胞程序性死亡的机制。我们重点研究了HIV达特基因在这一过程中的作用。达特可以通过改变各种酶的活性来调节细胞的氧化还原状态，以使细胞状态向促氧化条件转变。我们已经表明，改变的氧化还原状态可以导致细胞凋亡死亡。目前，我们正在研究达特和TNF-α相互作用介导的细胞死亡的调节以及p53和氧化应激在该过程中的作用。我们已经产生了几个细胞系，含有组成型激活的达特。在这些细胞中，达特增强了TNF诱导的转录因子NF-κ-B的活化和细胞毒性。此外，我们已经表明，TNF诱导的毒性是由TNFRI介导的。此外，我们已经表明，添加重组可溶性HIV达特蛋白可以诱导TNFRI表达。通过增加TNFRI，达特能够增强TNF的作用。今年是该项目的最后一年，该项目的一些组成部分将在涉及cDNA微阵列的新项目#下继续进行。- 凋亡，达特，肿瘤坏死因子，NF-κ B，CAPE，氧化应激

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 andTNF-alpha as well as the role of p53 and oxidant stressors in the process. 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. This is the final year for this project, some components of this project will be continued under a new project # involving cDNA microarrays. - apoptosis, tat, tumor necrosis factor, NF-kappa B, CAPE, oxidative stress