JC Polyomavirus Abundance and Distribution in Progressive Multifocal Leukoencephalopathy (PML) Brain Tissue Implicates Myelin Sheath in Intracerebral Dissemination of Infection
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- Journal Article
- Biology and Life Sciences
- Anatomy
- Nervous System
- Central Nervous System
- Medicine and Health Sciences
- Cell Biology
- Cellular Types
- Animal Cells
- Neurons
- Nerve Fibers
- Axons
- Neuroscience
- Cellular Neuroscience
- Clinical Medicine
- Clinical Immunology
- Autoimmune Diseases
- Multiple Sclerosis
- Immunology
- Neurology
- Demyelinating Disorders
- Neurodegenerative Diseases
- Microbiology
- Virology
- Viral Replication
- Viral Packaging
- Glial Cells
- Macroglial Cells
- Astrocytes
- Specimen Preparation and Treatment
- Staining
- Cell Staining
- Myelin Sheath
- Histochemistry and Cytochemistry Techniques
- Immunohistochemistry Techniques
- Immunologic Techniques