MOLECULAR PATHOGENESIS OF JC VIRUS & PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

JC病毒引起进行性胰腺炎发病机制的研究 脑白质病（PML）是JCV潜伏期机制研究热点 组织、病毒活化和运输到大脑以及转录 控制病毒基因表达。 实验在 临床、生物和分子水平。 使用PCR分析，来自 在骨髓中发现了疑似潜伏感染的淋巴细胞， 超过90%的PML患者的外周淋巴细胞，特别是 艾滋病是潜在的免疫系统疾病。 JCV DNA是 在超过50%的免疫抑制个体中也发现， PML确定他们有发生PML的风险。 DNA序列 对几名PML患者的调控区的分析表明， 原型（两个98碱基对重复单元）序列排列在 但大脑中的DNA序列发生了严重重排。 JCV 在Wiskott/Aldrich综合征中也首次发现了DNA 患者在骨髓和脑活检，并在骨髓和 治疗时在PML发生前三年采集的肾脏组织 脾切除术 这一独特的PML病例研究突出了以下观察结果： 骨髓细胞中的JCV潜伏期。 这些结果表明 JCV可通过血行途径传播至CNS，可能通过 一种B淋巴细胞载体。 为了检测病毒表达的分子控制， 检测了人胎脑和人B细胞的核蛋白 因为它们能够与JCV调节区结合。 蛋白质 来自这两个来源的因子能够结合几个位点， 含有NF-1蛋白的识别序列。 一个c-jun样因子 也能与调控区结合。 NF-1和c-jun结合 部位相邻或重叠。 审查 大脑中表达的许多其他基因的调控区域， MBP、GFAP、PLP、S100 B、NF-L和pro-ENK也显示它们在细胞内表达。 含有NF- 1和激活蛋白的相邻结合位点 在mRNA起始位点的上游。 这些结果表明 它们有共同的因子来调节这些基因， 组织特异性方式。

Investigations of the pathogenesis of JC Virus induced progressive leukoencephalopathy (PML) focus on mechanisms of latency of JCV in human tissues, viral activation and transport to the brain and transcriptional control of viral gene expression. Experiments are conducted at the clinical, biological and molecular levels. Using PCR analysis, JCV from suspected latently infected lymphocytes in bone marrow has been found in peripheral lymphocytes in more than 90% of PML patients, particularly individuals with AIDS as the underlying immune disorder. JCV DNA was also found in greater than 50% of immune suppressed individuals without PML identifying them at risk for the development of PML. DNA sequence analysis of the regulatory region from several PML patients demonstrated the prototype (two 98 base pair repeat units) sequence arrangement in peripheral blood but a greatly rearranged DNA sequence in the brain. JCV DNA was also found for the first time in a Wiskott/Aldrich syndrome patient in biopsies of bone marrow and brain, and in bone marrow and kidney tissues taken three years prior to PML at the time of therapeutic splenectomy. This unique case study of PML highlights the observation of JCV latency in marrow cells of the marrow. These results suggest that JCV could be spread to the CNS by a hematogenous route, possibly through a B lymphocyte vector. To examine molecular control of viral expression, nuclear proteins from human fetal brain and human B cells were examined for their ability to bind to the JCV regulatory region. A protein factor(s) from both of these sources was able to bind several sites which contain the recognition sequence for a NF-1 protein. A c-jun like factor was also able to bind the regulatory region. The NF-1 and c-jun binding sites were either adjacent or overlapped each other. Examination of the regulatory regions of many other genes expressed in the brain such as MBP, GFAP, PLP, S100B, NF-L, and pro-ENK revealed that they also appear to contain adjacent binding sites for NF- 1 and an activator protein immediately upstream from the mRNA start site. These results suggest that they share common factors which regulate these genes in a tissue-specific manner.