JC virus (JCV) is the causative agent of the human CNS demyelinating disease progressive multifocal leukoencephalopathy (PML). The mechanism by which demyelination occurs in the presence of this ubiquitous virus is not fully understood. However, PML occurs under conditions of immunosuppression, which permits the virus to undergo a lytic cycle of replication. The lytic cycle of JCV is initiated specifically in glial cells through transcription of the JCV early gene for the viral T- antigen. Prior studies of transgenic CD1 mice that express this gene and its promoter have shown that JCV T-antigen expression has led to a variable degree of CNS dysmyelination in a dose-dependent fashion. In vitro data from our laboratory demonstrate a dose-dependent trans-acting suppression of myelin basic protein (MBP) promoter activity by the T- antigen, suggesting that JCV early gene product expression may play a crucial role in regulating the expression of myelin gene products and thus lead to demyelination.
the aim of this project is to determine the impact of JCV T-antigen on the development and maintenance of CNS myelin. the original line of JCV T-antigen CD1 transgenic mice is now available for study in our laboratory. However, an additional transgenic line will be developed to examine, in depth, viral-induced dysmyelination in whole animal system that resembles JCV-induced PML in immunosuppressed humans. The experimental design includes: (i) analysis of myelin formation and expression of myelin genes, i.e. myelin basic protein, at the transcriptional and post-transcriptional levels in T-antigen-producing transgenic lines during brain development; (ii) identification of the cis-acting element responsive to the T-antigen that is located in the MBP 5' upstream sequence, and identification of the cellular factor(s) that interacts with the cis-acting sequences and trans-suppresses the MBP promoter; (iii) examination of the biological function of the T-antigen- target sequence in suppressing the MBP promoter in tissue culture and in a whole animal system, and genetic manipulation of a transgenic line containing a multimerized copy of the target to impair interaction of the trans-suppressor protein with the endogenous MBP promoter. The information obtained from these experiments should enhance our understanding of the pathogenesis of PML and provide clues regarding the development of demyelinating disease at the molecular level.

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Mcp Hahnemann University
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