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Measurement of BK-polyomavirus Non-Coding Control Region Driven Transcriptional Activity Via Flow Cytometry
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Lymphocyte gene expression and JC virus noncoding control region sequences are linked with the risk of progressive

Leslie J Marshall1, Michael W Ferenczy, Elizabeth L Daley

  • 1Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Journal of Virology
|February 21, 2014
PubMed

Insights

Progressive multifocal leukoencephalopathy (PML) risk increases when unique viral DNA sequences interact with the Spi-B protein, which is affected by natalizumab therapy. This synergy between viral genetics and drug-induced changes may heighten PML susceptibility.

Area of Science:

  • Neurovirology
  • Molecular Biology
  • Immunology

Background:

  • Progressive multifocal leukoencephalopathy (PML) is a serious demyelinating disease of the central nervous system.
  • JC virus (JCV) noncoding control regions (NCCRs) regulate viral gene expression.
  • Natalizumab therapy is a known risk factor for PML.

Purpose of the Study:

  • To investigate the differences in early viral gene expression between PML-derived and kidney-associated JCV NCCRs.
  • To identify the role of transcription factors, specifically Spi-B, in regulating JCV gene expression in the context of PML.

Main Methods:

  • Comparative analysis of JCV NCCR sequences from PML and kidney tissues.
  • Reporter assays to measure viral gene expression.
  • Electrophoretic mobility shift assays (EMSAs) to assess transcription factor binding.

Main Results:

  • PML-derived NCCRs showed significantly greater early viral gene expression compared to kidney-associated NCCRs.
  • The transcription factor Spi-B preferentially bound to unique sites within PML-associated NCCRs.
  • Spi-B upregulation in B cells during natalizumab therapy was observed.

Conclusions:

  • Unique binding sites for Spi-B in PML-derived NCCRs enhance early viral gene expression.
  • Natalizumab-induced upregulation of Spi-B in B cells may contribute to PML pathogenesis.
  • The interplay between JCV sequence variation and drug-induced cellular changes increases PML risk.

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