title: Frequent infection of cerebellar granule cell neurons by polyomavirus JC in progressive multifocal leukoencephalopathy.
abstract: Progressive multifocal leukoencephalopathy (PML) occurs most often in immunosuppressed individuals. The lesions of PML result from astrocyte and oligodendrocyte infection by the polyomavirus JC (JCV); JCV has also been shown to infect and destroy cerebellar granule cell neurons (GCNs) in 2 human immunodeficiency virus (HIV)-positive patients. To determine the prevalence and pattern of JCV infection in GCNs, we immunostained formalin-fixed paraffin-embedded cerebellar samples from 40 HIV-positive and 3 HIV-negative PML patients for JCV, and glial and neuronal markers. The JCV infection was detected in 30 patients (70%); 28 (93%) of them had JCV-infected cells in the GC layer; JCV-infected GCNs were demonstrated in 15 (79%) of 19 tested cases. The JCV regulatory T antigen was expressed more frequently and abundantly in GCNs than JCV VP1 capsid protein. None of 37 HIV-negative controls but 1 (3%) of 35 HIV-positive subjects without PML had distinct foci of JCV-infected GCNs. Thus, JCV infection of GCNs is frequent in PML patients and may occur in the absence of cerebellar white matter demyelinating lesions. The predominance of Tantigen over VP1 expression in GCNs suggests that they may be the site of early or latent central nervous system JCV infection. These results indicate that infection of GCNs is an important, previously overlooked, aspect of JCV pathogenesis in immunosuppressed individuals.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Wüthrich
authors.forename: Yi Min
authors.initials: YM
authors.lastname: Cheng
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Joseph
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.forename: Curt
authors.initials: C
authors.lastname: Beckwith
authors.forename: Edward
authors.initials: E
authors.lastname: Stopa
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Bell
authors.forename: Igor J
authors.initials: IJ
authors.lastname: Koralnik
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000473:pathology / Q000821:virology; D000328:Adult; D000368:Aged; D000957:Antigens, Viral, Tumor / Q000378:metabolism; D036022:Capsid Proteins / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002531:Cerebellum / Q000473:pathology*; D003711:Demyelinating Diseases / Q000209:etiology / Q000821:virology; D005260:Female; D006801:Humans; D007577:JC Virus / Q000472:pathogenicity*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000150:complications / Q000473:pathology* / Q000821:virology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000473:pathology* / Q000821:virology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D015678:Viral Structural Proteins / Q000378:metabolism
chemical_list: D000957:Antigens, Viral, Tumor; D036022:Capsid Proteins; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D015678:Viral Structural Proteins; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D010751:Phosphopyruvate Hydratase