INDUCTION OF APOPTOSIS BY HIV-1 VPR

来自HIV-1的VPR基因编码96个氨基酸的蛋白质， 诱导受感染淋巴细胞凋亡。VPR独立诱导细胞凋亡 p53的存在和功能，并以一种由 激活胱氨酸-天冬氨酸蛋白酶3和8。的目的 目前的研究是在分子水平上了解 HIV-1 VPR诱导细胞凋亡。研究将首先检查以下可能性： VPR激活细胞凋亡途径，这些途径通常对死亡起反应 受体激活或DNA损伤。接下来将进行研究， 存活途径的激活或失活程度通常 阻止进入细胞凋亡。然后将检查宏程序以确定 艾滋病毒-1长期慢性感染的影响以及与艾滋病的关系 凋亡最后，研究将检查基因表达模式， 试图识别转录被修饰的未定义的细胞基因 VPR诱导的细胞凋亡。该提案的具体目标是：目标1。到 定义VPR激活的凋亡信号级联。目标2.到 检测VPR诱导的细胞凋亡中存活途径的作用。目标3。到 检查VPR对原代巨噬细胞活力的影响。目标4。到 鉴定VPR诱导凋亡过程中差异表达的细胞基因。

The VPR gene from HIV-1 encodes a 96 amino acid protein that induces apoptosis in infected lymphocytes. VPR induces apoptosis independently of the presence and function of p53, and in a manner that is mediated by activation of the cystine-aspartate proteases 3 and 8. The objective of the present study is to understand at a molecular level the mechanisms by which HIV-1 VPR induces apoptosis. Studies will first examine the possibility that VPR activates apoptosis pathways that normally function in response to death receptor activation or DNA damage. Studies will next be conducted to examine the degree of activation or inactivation of survival pathw0ays that normally prevent entry into apoptosis. Macrophages will then be examined to determine the impact of long-term, chronic infection by HIV-1 and the relationship to apoptosis. And lastly, studies will examine patterns of gene expression in an attempt to identify undefined cellular genes whose transcription is modified during VPR induced apoptosis. Specific aims of this proposal are: aim 1. To define the apoptosis signaling cascade that is activated by VPR. Aim 2. To examine the role of the survival pathway in VPR induced apoptosis. Aim 3. To examine the effect of VPR on the viability of primary macrophages. Aim 4. To identify differentially expressed cellular genes during VPR induced apoptosis.