Enam Sahnila, Sweet Thersa M, Amini Shohreh, Khalili Kamel, Del Valle Luis
Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pa, USA.
Arch Pathol Lab Med. 2004 Mar;128(3):282-91. doi: 10.5858/2004-128-282-EFIOTG.
Progressive multifocal leukoencephalopathy is a fatal demyelinating disease of the central nervous system frequently seen in patients with impaired immune systems, particularly acquired immunodeficiency syndrome. JC virus (JCV), a human neurotropic polyomavirus, is the etiologic infectious agent of this disease.
The significantly higher incidence of progressive multifocal leukoencephalopathy in patients with acquired immunodeficiency syndrome than in patients with other immunosuppressive conditions suggests that molecular interactions between human immunodeficiency virus 1 and JCV, via the Tat protein, are responsible for the activation of the JCV enhancer/promoter and the development of progressive multifocal leukoencephalopathy. An indirect mechanism through activation of cytokines, such as transforming growth factor beta1 and Smads 3 and 4, may also be responsible for the enhancement of JCV gene expression.
Immunohistochemical analysis in progressive multifocal leukoencephalopathy samples and chloramphenicol acetyl transferase assays on cell cultures were performed to corroborate this hypothesis.
The JCV capsid protein VP-1 was found in the nuclei of oligodendrocytes and in the nuclei and cytoplasm of bizarre astrocytes. Human immunodeficiency virus proteins, including p24 and Tat, were detected in the cytoplasm of astrocytes. Tat, but not p24, was detected in oligodendrocytes, suggesting that extracellular Tat accumulates in the nuclei of oligodendrocytes, where JCV gene transcription takes place. High levels of transforming growth factor beta1 and Smads 3 and 4 were detected in JCV-infected oligodendrocytes. Results from in vitro studies confirm activation of the JCV early and late promoters by Smads 3 and 4.
These observations support our model, suggesting that the induction of transforming growth factor beta1 by human immunodeficiency virus 1 Tat can stimulate its downstream factors, including Smads 3 and 4, which in turn augment transcription of the JCV promoter in glial cells.
进行性多灶性白质脑病是一种致命的中枢神经系统脱髓鞘疾病，常见于免疫系统受损的患者，尤其是获得性免疫缺陷综合征患者。JC病毒（JCV）是一种嗜人神经多瘤病毒，是该疾病的病原性感染因子。
获得性免疫缺陷综合征患者中进行性多灶性白质脑病的发病率显著高于其他免疫抑制状态的患者，这表明人类免疫缺陷病毒1与JCV之间通过Tat蛋白发生的分子相互作用，导致了JCV增强子/启动子的激活以及进行性多灶性白质脑病的发展。通过激活细胞因子（如转化生长因子β1以及Smad 3和Smad 4）的间接机制，也可能导致JCV基因表达增强。
对进行性多灶性白质脑病样本进行免疫组织化学分析，并在细胞培养物上进行氯霉素乙酰转移酶测定，以证实这一假设。
在少突胶质细胞的细胞核以及奇异星形胶质细胞的细胞核和细胞质中发现了JCV衣壳蛋白VP-1。在星形胶质细胞的细胞质中检测到了包括p24和Tat在内的人类免疫缺陷病毒蛋白。在少突胶质细胞中检测到了Tat，但未检测到p24，这表明细胞外Tat在少突胶质细胞的细胞核中积累，而JCV基因转录就在此处发生。在JCV感染的少突胶质细胞中检测到高水平的转化生长因子β1以及Smad 3和Smad 4。体外研究结果证实Smad 3和Smad 4可激活JCV的早期和晚期启动子。
这些观察结果支持了我们的模型，表明人类免疫缺陷病毒1 Tat诱导转化生长因子β1可刺激其下游因子，包括Smad 3和Smad 4，进而增强神经胶质细胞中JCV启动子的转录。
