MOLECULAR PATHOGENESIS OF JC VIRUS & PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

我们之前已经证明了核苷酸类似物的有效性， 阿糖胞苷(ARA-C)阻断JC病毒DNA复制 进行性多灶性白质脑病(PML)的病因。 使用的ARA-C浓度对人神经胶质细胞在 文化。65例艾滋病患者经活检证实为PML(实验室 用原位DNA杂交法检测病毒确认诊断 DNA)都参与了这项研究。外周血和脑脊液 是从这些患者身上提取的，作为治疗的继续，并进行了病毒检测 DNA在几个样本中，在B淋巴细胞中发现了病毒DNA 而不是T细胞。这一观察结果与之前的一致 骨髓和脾B细胞感染的临床标本。十五 患者接受ARA-C鞘内给药。腰椎 对这一组进行了穿刺术。样本是在一个 纵向研究。脑脊液样本的聚合酶链式反应分析显示，79%的 接受测试的患者在脑脊液中的某个时间有JCV PML。然而，在4例患者的脑脊液中没有JCV的证据。 他们的治疗方案。这些患者体内也没有病毒DNA 他们的鲜血。这项研究现已完成。这些数据正在评估中。它 脑脊液中没有病毒DNA的患者似乎有一种 与其他组相比，寿命延长。 我们之前已经确定JCV能够感染基质细胞 来源于人扁桃体组织和人造血干细胞 细胞。这些细胞是CD34+，并将分化为淋巴样细胞 血统。向单核/巨噬细胞分化的CD34+细胞 血统对JCV感染不敏感。我们已经成立了一家公司 淋巴和神经胶质细胞在JCV感染发病机制中的联系 导致人脑脱髓鞘。我们还放映了50多部 扁桃体组织，并在15%的样本中发现JCV DNA。 JCV的宿主范围也扩大到包括一种胶质瘤细胞系 来源于神经母细胞瘤细胞。目前已知的JCV主机范围包括 胶质细胞和B淋巴细胞谱系。它们的分子相似性 这些细胞的JCV基因表达与核因子-1直接相关 具有转录功能的DNA结合蛋白家族。我们有 也使得在JCV中表达NF-1类的细胞系不允许 宿主细胞。核因子-1/D类蛋白的表达传递通透性 与感染有关。

We had previously demonstrated the effectiveness of the nucleotide analog, cytosine arabinoside (ARA-C) to block replication of the JC viral DNA the etiologic agent for progressive multifocal leukoencephalopathy (PML). Concentrations of ARA-C used were not toxic to the human glial cells in culture. Sixty-five AIDS patients with biopsy proven PML (the laboratory confirms the diagnosis using in situ DNA hybridization to detect viral DNA) were enrolled in the study. Peripheral blood and cerebrospinal fluid was taken from these patients as treatment proceeds and tested for viral DNA. In several samples, the viral DNA was identified in the B lymphocyte population and not T cells. This observation is consistent with previous clinical samples of B cell infection in bone marrow and spleen. Fifteen patients were treated with ARA-C using intrathecal administration. Lumbar punctures were performed on this group. Samples were collected in a longitudinal study. PCR analysis of CSF samples revealed that 79% of the patients tested had JCV in their CSF at some time during the course of PML. In 4 cases, however, there was no evidence of JCV in their CSF during their treatment regime. These patients also did not have viral DNA in their blood. The study is now completed. The data are being evaluated. It does appear that the patients with no viral DNA in the CSF have an extended life span compared with the other groups. We had previously determined that JCV is able to infect stromal cells derived from human tonsillar tissue as well as human hematopoietic stem cells. These cells are CD34+ and will differentiate into a lymphoid lineage. CD34+ cells that differentiate toward a monocyte/macrophage lineage are not susceptible to JCV infection. We have established a firm link between lymphoid and glial cells in the pathogenesis of JCV infection leading to demyelination in the human brain. We have also screened over 50 tonsil tissues and found JCV DNA in 15% of these samples. The host range of JCV is also expanded to include a glioma cell line derived from neuroblastoma cells. JCV host range is now known to include cells of glial and B lymphocyte lineage. The molecular similarities of these cells for JCV gene expression directly correlated with the NF-1 family of DNA binding proteins which function for transcription. We have also made an NF-1 class of expressing cell line in a JCV non permissive host cell. The expression of NF-1/D class protein conveys permissiveness to infection.