Manley Kate, O'hara Bethany A, Gee Gretchen V, Simkevich Carl P, Sedivy John M, Atwood Walter J
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA.
J Virol. 2006 Dec;80(24):12079-85. doi: 10.1128/JVI.01456-06. Epub 2006 Oct 11.
The human polyomavirus JC virus (JCV) infects 70% of the population worldwide. In immunosuppressed patients, JCV infection can lead to progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system (CNS). The majority of PML cases occur in the setting of human immunodeficiency virus (HIV) infection, and it has been suggested that the link between HIV and the development of PML is in part related to the production of numerous cytokines in the CNS during HIV infection. To examine the link between the expression of inflammatory cytokines and JCV infection, we tested an anti-inflammatory compound, cyclosporine A (CsA), for its ability to block JCV infection of glial cells. We found that CsA inhibited JCV infection by preventing the activation of the transcription factor nuclear factor of activated T cells 4 (NFAT4). Luciferase reporter assays and chromatin immunoprecipitation assays revealed that NFAT4 directly bound the JCV promoter during infection and was important for the activation of both early and late transcription. In addition, the expression of the JCV early viral gene products increased NFAT activity to further aid viral transcription. The necessity of NFAT for JCV infection suggests that calcium signaling and the activation of NFAT in glial cells are required for JCV infection of the CNS.
人类多瘤病毒JC病毒（JCV）感染了全球70%的人口。在免疫抑制患者中，JCV感染可导致进行性多灶性白质脑病（PML），这是一种致命的中枢神经系统（CNS）脱髓鞘疾病。大多数PML病例发生在人类免疫缺陷病毒（HIV）感染的情况下，有人认为HIV与PML发生之间的联系部分与HIV感染期间中枢神经系统中多种细胞因子的产生有关。为了研究炎性细胞因子表达与JCV感染之间的联系，我们测试了一种抗炎化合物环孢素A（CsA）阻断神经胶质细胞JCV感染的能力。我们发现CsA通过阻止活化T细胞核因子4（NFAT4）转录因子的激活来抑制JCV感染。荧光素酶报告基因检测和染色质免疫沉淀检测表明，NFAT4在感染期间直接结合JCV启动子，对早期和晚期转录的激活都很重要。此外，JCV早期病毒基因产物的表达增加了NFAT活性，以进一步促进病毒转录。NFAT对JCV感染的必要性表明，神经胶质细胞中的钙信号传导和NFAT的激活是JCV感染中枢神经系统所必需的。
