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Updated: Aug 5, 2026

Isolation of Brain-infiltrating Leukocytes
Published on: June 13, 2011
JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue
Keith A Wharton1, Catherine Quigley1, Marian Themeles1
1Translational Pathology Laboratory, Biogen Inc., Cambridge, MA, United States of America.
Abstract:
Over half of adults are seropositive for JC polyomavirus (JCV), but rare individuals develop progressive multifocal leukoencephalopathy (PML), a demyelinating JCV infection of the central nervous system. Previously, PML was primarily seen in immunosuppressed patients with AIDS or certain cancers, but it has recently emerged as a drug safety issue through its association with diverse immunomodulatory therapies. To better understand the relationship between the JCV life cycle and PML pathology, we studied autopsy brain tissue from a 70-year-old psoriasis patient on the integrin alpha-L inhibitor efalizumab following a ~2 month clinical course of PML. Sequence analysis of lesional brain tissue identified PML-associated viral mutations in regulatory (non-coding control region) DNA, capsid protein VP1, and the regulatory agnoprotein, as well as 9 novel mutations in capsid protein VP2, indicating rampant viral evolution. Nine samples, including three gross PML lesions and normal-appearing adjacent tissues, were characterized by histopathology and subject to quantitative genomic, proteomic, and molecular localization analyses. We observed a striking correlation between the spatial extent of demyelination, axonal destruction, and dispersion of JCV along white matter myelin sheath. Our observations in this case, as well as in a case of PML-like disease in an immunocompromised rhesus macaque, suggest that long-range spread of polyomavirus and axonal destruction in PML might involve extracellular association between virus and the white matter myelin sheath.
Insights
JC polyomavirus (JCV) can cause progressive multifocal leukoencephalopathy (PML). This study found JCV spreads along myelin sheaths, potentially explaining axonal destruction in PML patients.
Area of Science:
- Neurovirology
- Immunology
- Neuropathology
Background:
- JC polyomavirus (JCV) infection is common, but progressive multifocal leukoencephalopathy (PML) is rare, typically in immunosuppressed individuals.
- PML is an emerging drug safety concern linked to immunomodulatory therapies, including efalizumab.
Purpose of the Study:
- To investigate the relationship between JCV life cycle and PML pathology.
- To analyze viral evolution and spread in PML brain tissue from an efalizumab-treated patient.
Main Methods:
- Histopathology and quantitative genomic, proteomic, and molecular localization analyses of autopsy brain tissue.
- Sequence analysis of regulatory DNA, VP1, VP2, and agnoprotein in lesional brain tissue.
Main Results:
- Identified PML-associated mutations in JCV regulatory DNA, VP1, and agnoprotein, plus novel VP2 mutations, indicating viral evolution.
- Observed a strong correlation between demyelination, axonal destruction, and JCV dispersion along white matter myelin sheaths.
- Findings were consistent with a similar case in an immunocompromised rhesus macaque.
Conclusions:
- JCV undergoes significant evolution within PML lesions.
- Long-range spread of JCV and axonal destruction in PML may involve extracellular association with the white matter myelin sheath.
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