MOLECULAR PATHOGENESIS OF JC VIRUS & PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

JC 病毒的分子发病机制

• 批准号: 2579509
• 负责人: E O MAJOR
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2579509
• 关键词: AIDS therapy; B lymphocyte; DNA replication; Polyomavirus hominis 2; biopsy; cerebrospinal fluid; clinical research; clinical trials; cytosine arabinoside; glia; human immunodeficiency virus 1; human subject; human therapy evaluation; interleukin 1; molecular pathology; neurotrophic factors; northern blottings; nucleotide analog; peripheral blood vessel; progressive multifocal leukoencephalopathy; tissue /cell culture; transcription factor; tumor necrosis factor alpha; virus DNA; virus genetics; virus infection mechanism

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.

该实验室参与了一项II期临床试验， 治疗艾滋病患者的脱髓鞘疾病，PML。我们有 先前证明了核苷酸类似物的有效性， 阿糖胞苷（ARA-C）阻断病毒DNA的复制。 使用的ARA-C浓度对人神经胶质细胞没有毒性， 文化 目前38例艾滋病患者活检证实PML（ 实验室使用原位DNA杂交确认诊断， 检测病毒DNA）已入组研究。 我们研究的 这些患者的外周血和脑脊液作为治疗 收益。 在几乎所有的情况下，病毒DNA都在血液中被发现。 在几个样本中，在B淋巴细胞中鉴定出病毒DNA 而不是T细胞。 这一观点与此前的观点一致。 骨髓和脾脏中B细胞感染的临床样本。 的 治疗方案将持续到最多90名患者 已注册或已满两年。 研究还为时过早， 确定药物的功效。 分子生物学研究现在将B和神经胶质细胞易感性联系起来 在转录水平上与JCV感染相关。 的成员 转录因子家族，NF-1，似乎是高表达的， 通过北方印迹分析在B细胞系中发现， 乘。 进一步分析转染到非肿瘤细胞中的NF-1/AT 1克隆， 允许的细胞正在做。 然而，NF-1因子不是 在使用TNF-α的细胞因子刺激下其活性增加，或 IL-1 β。 这些细胞因子刺激NF-κ B转录因子 这是HIV-1在神经胶质细胞中增殖所必需的。 不 JCV可能使用NF-kB进行转录，也不可能 感染被细胞因子增强。