regulation of human neurotropic jc virus replication by alternative splicing factor sf2asf in glial cells调节人类的亲神经的可变剪接因子sf2asf jc病毒复制的神经胶质细胞.pdfVIP

Regulation of Human Neurotropic JC Virus Replication by Alternative Splicing Factor SF2/ASF in Glial Cells Ilker Kudret Sariyer, Kamel Khalili* Department of Neuroscience and Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America Abstract Background: The human neurotropic virus, JC virus (JCV), is the etiologic agent of the fatal demyelinating disease of the central nervous system, Progressive Multifocal Leukoencephlopathy (PML) that is seen primarily in immunodeficient individuals. Productive infection of JCV occurs only in glial cells, and this restriction is, to a great extent, due to the activation of the viral promoter that has cell type-specific characteristics. Earlier studies led to the hypothesis that glial-specific activation of the JCV promoter is mediated through positive and negative transcription factors that control reactivation of the JCV genome under normal physiological conditions and suppress its activation in non-glial cells. Methodololgy/Principal Findings: Using a variety of virological and molecular biological approaches, we demonstrate that the alternative splicing factor SF2/ASF has the capacity to exert a negative effect on transcription of the JCV promoter in glial cells through direct association with a specific DNA sequence within the viral enhancer/promoter region. Our results show that down-regulation of SF2/ASF in fetal and adult glial cells increases the level of JCV gene expression and its replication indicating that negative regulation of the JCV promoter by SF2/ASF may control reactivation of JCV replication in brain. Conclusions/Significance: Our results establish a new regulatory role for SF2/ASF in controlling gene expression at the transcriptional level. Citation: Sariyer IK, Khal