The molecular pathogenesis of demyelination and CNS tumors induced by the neurotropic papovavirus, JCV

Ganesh Venkataram Raj, Thomas Jefferson University

Abstract

JC virus (JCV) is a common human neurotropic papovavirus, and is thought to be the etiological agent of a fatal demyelinating disorder, Progressive Multifocal Leucoencephalopathy (PML). Individuals with PML have a striking incidence of immune dysregulation, and often present with a chronic and profound cellular immunosuppression, caused by drugs, chronic illness, cancers or recently, AIDS. Since JCV is latent in most individuals, a logical hypothesis would link the immunodysregulation with the reactivation from latency of the virus, the ensuing lytic infection of oligodendrocytes and subsequent demyelination and disease. Immunosuppressive conditions are associated with a massive alteration in the level of cytokines: some like TGF-$\beta$1 are elevated, others like IL-2 are decreased in AIDS- associated PML. Understanding the effect of cytokines on the expression of JCV may potentially explain the reactivation of JCV from latency. My thesis work revolves around the understanding of inducible cellular and viral factors involved in the reactivation of JCV from latency. Towards this end, analyses of the effect of cytokines on JC viral late gene expression were performed, and their responsive cis- and trans-acting elements were characterized. A novel inducible transcription factor, GBP-i, which interacts with the viral origin of DNA replication, was identified. GBP-i regulates JCV gene expression bidirectionally and appears to be rapidly induced at the transcriptional level. Another inducible transcription factor, the NF-$\kappa$B appeared to interact with another cellular protein, the YB-1 protein and mediate its regulation of the JCV promoter through both the NF-$\kappa$B binding site and the YB-1 binding site on the viral promoter. These findings enhance the scope of inducible transcriptional regulation of the JC virus. The alteration in the cytokine profile seen in immunosuppressed patients also prompted analyses of the regulation of the expression of the individual cytokines. Examination of the effect of the immune system on TGF-$\beta$ gene expression in glial cells demonstrates that TGF-$\beta$2 expression is dramatically enhanced by the secretions from cells of the immune system. The activation of TGF-$\beta$2 is associated with the loss of binding activity for a glial labile repressor protein, the GLRP. Additional analyses of the regulation of TGF-$\beta$ gene expression also implicates a role for the cell cycle regulators, pRb, E2F and p53. Interestingly, there appears to be a complex feedback loop between the cell cycle regulators and the expression of TGF-$\beta .$ Since JCV causes CNS tumors in experimental animals, including hamsters, initial analyses of the expression of distinct oncogenes and tumor suppressor genes were performed. Clonal cell lines derived from hamster tumors were established and characterized. Distinct E2F-associated transcription factors, the GEAPs were identified in JCV-transformed glial cells. GEAPs significantly enhance the expression of cellular promoters driven by the consensus E2F site, and may contribute to transforming prowess of the JC virus.

Subject Area

Microbiology|Neurology|Oncology

Recommended Citation

Raj, Ganesh Venkataram, "The molecular pathogenesis of demyelination and CNS tumors induced by the neurotropic papovavirus, JCV" (1997). ProQuest ETD Collection - Thomas Jefferson University. AAI9727335.
https://jdc.jefferson.edu/dissertations/AAI9727335

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