CHARACTERIZATION OF THE JC VIRUS EARLY PROMOTER IN PML

Project: Research project

Project Details

Description

The experiments in this application are designed to elucidate the biology
of an oligodendrocyte-specific virus, JC virus. JC virus causes a fatal
demyelinating disease (progressive multifocal leukoencephalopathy) of
immunosuppressed patients. Glial-specificity is controlled by the viral
promoter. We isolated JC viral promoters directly from the brains of
patients with PML. Each viral promoter contains an identical proximal
sequence (including an Spl binding site that we have recently
characterized) that is highly similar to myelin basic protein and
proteolipid protein promoters, but dissimilar to the original, culture
derived JC virus isolate (Mad-1 strain). We hypothesize that this
proximal, conserved promoter region contributes to the glial-specificity
of JC virus gene transcription

Our aims are to: 1) examine the transcriptional function and specificity
of the conserved JC virus promoter region using promoter-CAT constructs
in transfection assays, 2) to test the function and specificity of the
Spl binding site in the proximal JC virus promoter, using mutant
promoters in CAT assays and Spl overexpression, 3) to test the ability of
the chemotherapy agent mithramycin to inhibit Spl from binding to the JC
virus promoter and to specifically inhibit JC virus transcription (thus
becoming a potential therapeutic agent for PML), 4) to test JC virus
promoter activity following stable chromosomal integration using
retroviral vectors, 5) to isolate glial proteins that bind to the Spl
site. In addition we plan to examine JC virus promoters isolated from
healthy kidney to further identify sequences important for tissue
specificity. The results of these studies have implications for the
treatment of PML, for understanding glial-specific transcription, and for
the design of brain-specific gene therapy.
StatusNot started

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke

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