title: JC virus granule cell neuronopathy is associated with VP1 C terminus mutants.
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.
authors.affiliation: Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.|Division of Neurovirology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Dang
authors.affiliation: Department of Neurology, Emilio Ribas Institute of Infectious Disease, Sao Paulo, Brazil.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Vidal
authors.affiliation: Department of Neurology, Emilio Ribas Institute of Infectious Disease, Sao Paulo, Brazil.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Penalva de Oliveira
authors.affiliation: Departments of Neuroscience and Pathology, Mount Sinai School of Medicine, New York, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Simpson
authors.affiliation: Division of Neuropathology, Mount Sinai School of Medicine, New York, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Morgello
authors.affiliation: Division of Neurology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Hecht
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Long H
authors.initials: LH
authors.lastname: Ngo
authors.affiliation: Division of Viral Pathogenesis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.|Division of Neurovirology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Igor J
authors.initials: IJ
authors.lastname: Koralnik
mesh_terms: D000293:Adolescent; D000328:Adult; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002526:Cerebellar Diseases / Q000473:pathology / Q000821:virology*; D005260:Female; D006801:Humans; D007577:JC Virus / Q000737:chemistry / Q000235:genetics* / Q000302:isolation & purification* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009474:Neurons / Q000821:virology; D027601:Polyomavirus Infections / Q000473:pathology / Q000821:virology*; D016415:Sequence Alignment; D017384:Sequence Deletion; D014779:Virus Replication; D055815:Young Adult
chemical_list: D036022:Capsid Proteins; C062481:VP1 protein, polyomavirus