Progressive multifocal leukoencephalopathy (PML)-derived noncoding control region (NCCR) sequences permitted greater early viral gene expression than kidney-associated NCCR sequences. This was driven in part by binding of the transcription factor Spi-B to unique PML-associated Spi-B binding sites. Spi-B is upregulated in developing B cells in response to natalizumab therapy, a known risk factor for PML.
View Article and Find Full Text PDFJC virus (JCV) is a ubiquitous human polyomavirus that causes the demyelinating disease Progressive Multifocal Leukoencephalopathy (PML). JCV replicates in limited cell types in culture, predominantly in human glial cells. Following introduction of a replication defective SV40 mutant that expressed large T protein into a heterogeneous culture of human fetal brain cells, multiple phenotypes became immortalized (SVG cells).
View Article and Find Full Text PDFViral infections of the central nervous system (CNS) are of increasing concern, especially among immunocompromised populations. Rodent models are often inappropriate for studies of CNS infection, as many viruses, including JC virus (JCV) and HIV, cannot replicate in rodent cells. Consequently, human fetal brain-derived multipotential CNS progenitor cells (NPCs) that can be differentiated into neurons, oligodendrocytes, or astrocytes have served as a model in CNS studies.
View Article and Find Full Text PDFProgressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs.
View Article and Find Full Text PDFICP0 is a transcriptional activating protein required for the efficient replication and reactivation of latent herpes simplex virus 1 (HSV-1). Multiple regions of ICP0 contribute its activity, the most prominent of which appears to be the RING finger, which confers E3 ubiquitin ligase activity. A region in the C terminus of ICP0 has also been implicated in several activities, including the disruption of a cellular repressor complex, REST/CoREST/HDAC1/2/LSD1.
View Article and Find Full Text PDFPersisting latent herpes simplex virus genomes are to some degree found in a heterochromatic state, and this contributes to reduced gene expression resulting in quiescence. We used a relatively long-term quiescent infection model in human fibroblasts, followed by provision of ICP0 in trans, to determine the effects of ICP0 on the viral chromatin state as gene expression is reactivated. Expression of ICP0, even at low levels, results in a reduction of higher-order chromatin structure and heterochromatin on quiescent viral genomes, and this effect precedes an increase in transcription.
View Article and Find Full Text PDFThe ability of herpes simplex virus to persist in cells depends on the extent of viral-gene expression, which may be controlled by epigenetic mechanisms. We used quiescent infection with the viral mutants d109 and d106 to explore the effects of cell type and the presence of the viral protein ICP0 on the expression and chromatin structure of the human cytomegalovirus (HCMV) tk and gC promoters on the viral genome. Expression from the HCMV promoter on the d109 genome decreased with time and was considerably less in HEL cells than in Vero cells.
View Article and Find Full Text PDFHerpes Simplex Virus Type 1 (HSV-1) infection is widespread and causes significant disease. A number of prophylactic vaccine strategies have elicited protective immunity in animal models, but no human vaccine has yet been effective. Asymptomatic HSV-1 infection is common, demonstrating that the immune system is able to control infection, despite failure to clear the virus.
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