MOLECULAR PATHOGENESIS OF JC VIRUS & PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

该实验室参与了一项第二阶段临床试验，以 治疗艾滋病患者的脱髓鞘病，PML。我们有过 先前证明了核苷酸类似物的有效性， 阿糖胞苷(ARA-C)可阻断病毒DNA的复制。 使用的ARA-C浓度对人神经胶质细胞在 文化。目前有38名艾滋病患者经活检证实为PML( 实验室通过原位DNA杂交确认了诊断 检测病毒DNA)已经加入了这项研究。我们已经研究了 患者的外周血和脑脊液作为治疗 收益。在几乎所有的病例中，都在血液中发现了病毒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。这个 治疗方案将继续进行，直到最多90名患者 注册一两年已经过去了。现在研究还为时过早 确定药物的疗效。 分子生物学研究现在将B细胞和神经胶质细胞的易感性联系起来 在转录水平上对JCV感染的影响。该委员会的成员 转录因子家族，核因子-1，似乎是高表达的 通过Northern杂交分析在B细胞系中发现，这些B细胞株允许JCV 乘法。进一步分析核转录因子-1/AT1克隆在非小细胞肺癌中的表达 允许的牢房正在进行中。然而，核因子-1并不是 在细胞因子刺激下，使用肿瘤坏死因子α或 IL-1β。这些细胞因子刺激核因子-kB转录因子 这对HIV-1在神经胶质细胞中的增殖至关重要。它不是 JCV可能使用核因子-kB进行转录，JCV也不太可能 感染被细胞因子放大。

The laboratory has participated in a Phase II clinical trial for treatment of AIDS patients with the demyelinating disease, PML. We had previously demonstrated the effectiveness of the nucleotide analogue, cytosine arabinoside (ARA-C) to block replication of the viral DNA. Concentrations of ARA-C used were not toxic to the human glial cells in culture. Currently 38 AIDS patients with biopsy proven PML (the laboratory confirms the diagnosis using in situ DNA hybridization to detect viral DNA) have been enrolled in the study. We have examined the peripheral blood and cerebrospinal fluid from these patients as treatment proceeds. In almost all cases, viral DNA has been found in the blood. 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. The treatment protocol will continue until a maximum of 90 patients are enrolled or two years have elapsed. It is too early in the study to determine efficacy of the drug. Molecular biology studies are now linking B and glial cell susceptibility to JCV infection at the transcriptional level. A member of the transcription factor family, NF-1, appears to be highly expressed in found by Northern blot analysis in B cell lines that allow JCV to multiply. Further analysis of the NF-1/AT1 clone transfected into non- permissive cells is being done. The NF-1 factor, however, is not increased in its activity with cytokine stimulation using TNF-alpha or IL-1 beta. These cytokines stimulate the NF-kB transcription factor which is essential for HIV-1 multiplication in glial cells. It is not likely that JCV uses NF-kB for transcription nor is it likely that JCV infection is augmented by cytokines.