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Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein

Leonid Gorelik1, Carl Reid, Manuela Testa

  • 1Biogen IDEC Inc., Cambridge, MA, USA. leonid.gorelik@biogenidec.com

The Journal of Infectious Diseases
|June 2, 2011
PubMed

Insights

Mutations in the JC virus (JCV) VP1 protein may cause progressive multifocal leukoencephalopathy (PML) by altering viral binding. These VP1 mutations allow JCV to invade the brain while evading immune detection.

Area of Science:

  • Neurovirology
  • Molecular Biology
  • Immunology

Background:

  • Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by JC virus (JCV) infection of oligodendrocytes.
  • PML often occurs in immunocompromised individuals due to reactivation of a latent JCV infection.

Purpose of the Study:

  • To investigate the role of mutations in the JCV capsid viral protein 1 (VP1) in the pathogenesis of PML.
  • To understand how VP1 mutations affect JCV binding to host cells and influence brain invasion.

Main Methods:

  • Analysis of JCV VP1 sequences from cerebrospinal fluid, plasma, and urine of PML patients.
  • Production and characterization of VP1-derived virus-like particles (VLPs) with specific mutations.
  • Assessment of VLP binding to different cell types and their interaction with sialic acid.

Main Results:

  • JC virus (JCV) VP1 mutations were identified in the cerebrospinal fluid of most PML patients, correlating with disease onset.
  • Mutated VP1-derived VLPs exhibited altered hemagglutination and ganglioside specificity.
  • Mutant VLPs showed reduced binding to peripheral cells but retained binding to brain-derived cells, independent of sialic acid.

Conclusions:

  • JC virus (JCV) VP1 substitutions are acquired intrapatient and are associated with PML.
  • These mutations may facilitate JCV brain invasion by abrogating sialic acid binding to peripheral cells while maintaining sialic acid-independent binding to brain cells.

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