MOLECULAR PATHOGENESIS OF JC VIRUS & PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

JCV诱发的进行性多灶性病变的研究 脑白质病（PML）是在临床标本上进行的， 组织培养和宿主细胞的生化分析。 JCV DNA是 在超过90%的PML患者的外周淋巴细胞中检测到 PCR分析。 这些患者中的许多人有艾滋病作为潜在的 免疫紊乱 在HIV~1血清学阳性而无PML者中， 超过50%的人被发现在他们的外周血中有JCV 淋巴细胞 这后一组将处于发展PML的风险中， 未来 三年后，在骨髓和肾组织中发现了JCV DNA 在患有Wiskott-Aldrich综合征的患者的PML发作之前， 而后者在骨髓和大脑样本中发现， 尸检 后一种情况表明JCV可以潜伏在细胞中 在骨髓中，此外，在外周血中发现JCV 淋巴细胞，表明JCV可以通过淋巴细胞扩散到CNS。 血行途径 表达载体在基因的控制下， 原型Mad~1或“脑”型菌株Mad~8调节区是 来检测什么样的组织和细胞类型可以影响 JCV基因表达。 氯霉素乙酰转移酶和β- 半乳糖苷酶表达载体用于转染研究， 回答组织特异性和细胞特异性表达的问题 关于JCV 人胎儿细胞核蛋白的生化分析 研究了大脑和人类B细胞，以确定是否有类似的蛋白质 参与JCV基因在这些组织中的表达。 核 来自这两种人类细胞系的蛋白质能够特异性地 与JCV调节基因中相同的核苷酸序列相互作用 地区 其中一种蛋白质因子被鉴定为核因子。 NF~1蛋白和c~Jun样因子。 内 在JCV的调控区，存在多种NF~1蛋白结合 网站. c~Jun结合位点或相邻或重叠， NF~1结合位点位于调控区。 类似的 推测的NF~1和激活蛋白结合位点的关联， 在大脑中表达的许多其他基因中发现。 这些结果 表明人脑细胞和B细胞可能含有类似的因子 其可以调节JCV在这些组织中的表达。

Investigations of JCV~induced progressive multifocal leukoencephalopathy (PML) are being carried out on clinical specimens, in tissue culture, and biochemical analysis of host cells. JCV DNA was detected in peripheral lymphocytes in more than 90% of PML patients using PCR analysis. Many of these patients had AIDS as the underlying immune disorder. In HIV~1 seropositive individuals without PML, more than 50% of the individuals were found to have JCV in their peripheral lymphocytes. This later group would be at risk to develop PML in the future. JCV DNA was found in bone marrow and kidney tissue three years prior to the onset of PML in a patient with Wiskott~Aldrich syndrome, and latter found in bone marrow and brain samples taken at the time of autopsy. This latter case suggests that JCV can be latent in cells in bone marrow, and in addition, with the finding of JCV in peripheral lymphocytes, suggest that JCV could be spread to the CNS by a hematogenous route. Expression vectors under the control of the prototype Mad~1 or "brain" type strain Mad~8 regulatory region are being constructed to examine what tissue and cell type can influence JCV gene expression. Both chloramphenicol acetlytransferase and beta- galactosidase expression vectors are used in transfection studies to answer the question of tissue specific and cell specific expression of JCV. Biochemical analysis of nuclear proteins from human fetal brain and human B cells were studied to determine if similar proteins were involved in JCV gene expression in these tissues. Nuclear proteins from both these human cell lines were able to specifically interact with identical nucleotide sequences in the JCV regulatory region. One of these protein factors was identified as a nuclear factor~1 (NF~1) protein and the other a c~Jun like factor. Within the regulatory region of JCV, there were several NF~1 protein binding sites. The c~Jun binding sites were either adjacent or overlapped all the NF~1 binding sites located in the regulatory region. A similar association of putative NF~1 and activator protein binding sites was found in many other genes expressed in the brain. These results suggest that human brain cells and B cells may contain similar factors which can regulate the expression of JCV in these tissues.