JC virus granule cell neuronopathy is associated with VP1 C terminus mutants

Xin Dang, Jose E. Vidal, Augusto C.P. Penalva de Oliveira, David M. Simpson, Susan Morgello, Jonathan H. Hecht, Long H. Ngo, Igor J. Koralnik

Research output: Contribution to journalReview article

52 Scopus citations

Abstract

The polyomavirus JC (JCV) infects glial cells and causes progressive multifocal leukoencephalopathy (PML). We described a novel JCV-variant with a 10 bp deletion in the C terminus of the VP1 capsid protein, JCV GCN1. This mutant was associated with lytic infection of cerebellar granule cell neurons and cerebellar atrophy in an human immunodeficiency virus/PML patient. This condition, also observed independently from PML, was named JCV granule cell neuronopathy (JCV GCN). We characterized JCV mutations in cerebrospinal fluid (CSF) of four other JCV GCN patients, and reviewed the literature on 10 reported cases. The strain from one patient harboured the identical GCN1-deletion, while the other patients had novel mutations in the same area, named JCV GCN2-4, causing variable changes in VP1 structure. One patient also had wild-type JCV in the CSF. To study the mechanisms leading to JCV GCN, we compared viral replication kinetics from JCV GCN1 with the prototype JCV Mad1, the PML isolate JCV HWM and the prototype JCV Mad1D engineered with the GCN1-deletion. While all strains replicated at low levels in the medulloblastoma cell line DAOY from a cerebellar neuronal tumour, JCV Mad1 replicated better in astroglial SVG cells than JCV Mad1D or JCV GCN1 and all strains replicated at higher levels in COS-7 kidney cells, suggesting that the GCN1-deletion confers a disadvantage for viral growth in central nervous system white matter. The GCN1-deletion remained stable after 100 days in culture and VP1 protein was produced in all cell lines, indicating that JCV GCN1 is replication-competent in vitro. These data highlight an important and previously overlooked aspect of JCV-pathogenesis. Detection of GCN-type JCV strains in CSF may help clinicians diagnose JCV GCN.

Original languageEnglish (US)
Pages (from-to)175-183
Number of pages9
JournalJournal of General Virology
Volume93
Issue number1
DOIs
StatePublished - Jan 2012

ASJC Scopus subject areas

  • Virology

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    Dang, X., Vidal, J. E., Penalva de Oliveira, A. C. P., Simpson, D. M., Morgello, S., Hecht, J. H., Ngo, L. H., & Koralnik, I. J. (2012). JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. Journal of General Virology, 93(1), 175-183. https://doi.org/10.1099/vir.0.037440-0