title: Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity.
abstract: Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV) infection of oligodendrocytes, may develop in patients with immune disorders following reactivation of chronic benign infection. Mutations of JCV capsid viral protein 1 (VP1), the capsid protein involved in binding to sialic acid cell receptors, might favor PML onset. Cerebrospinal fluid sequences from 37/40 PML patients contained one of several JCV VP1 amino acid mutations, which were also present in paired plasma but not urine sequences despite the same viral genetic background. VP1-derived virus-like particles (VLPs) carrying these mutations lost hemagglutination ability, showed different ganglioside specificity, and abolished binding to different peripheral cell types compared with wild-type VLPs. However, mutants still bound brain-derived cells, and binding was not affected by sialic acid removal by neuraminidase. JCV VP1 substitutions are acquired intrapatient and might favor JCV brain invasion through abrogation of sialic acid binding with peripheral cells, while maintaining sialic acid-independent binding with brain cells.
authors.affiliation: Biogen IDEC Inc., Cambridge, MA, USA. leonid.gorelik@biogenidec.com
authors.forename: Leonid
authors.initials: L
authors.lastname: Gorelik
authors.forename: Carl
authors.initials: C
authors.lastname: Reid
authors.forename: Manuela
authors.initials: M
authors.lastname: Testa
authors.forename: Margot
authors.initials: M
authors.lastname: Brickelmaier
authors.forename: Simona
authors.initials: S
authors.lastname: Bossolasco
authors.forename: Annamaria
authors.initials: A
authors.lastname: Pazzi
authors.forename: Arabella
authors.initials: A
authors.lastname: Bestetti
authors.forename: Paul
authors.initials: P
authors.lastname: Carmillo
authors.forename: Ewa
authors.initials: E
authors.lastname: Wilson
authors.forename: Michele
authors.initials: M
authors.lastname: McAuliffe
authors.forename: Christopher
authors.initials: C
authors.lastname: Tonkin
authors.forename: John P
authors.initials: JP
authors.lastname: Carulli
authors.forename: Alexey
authors.initials: A
authors.lastname: Lugovskoy
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.forename: Shamil
authors.initials: S
authors.lastname: Sunyaev
authors.forename: Kenneth
authors.initials: K
authors.lastname: Simon
authors.forename: Paola
authors.initials: P
authors.lastname: Cinque
mesh_terms: D000328:Adult; D036022:Capsid Proteins / Q000235:genetics*; D002555:Cerebrospinal Fluid / Q000821:virology; D005260:Female; D006803:Human Development; D006801:Humans; D007577:JC Virus / Q000235:genetics* / Q000302:isolation & purification / Q000472:pathogenicity*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011991:Receptors, Virus / Q000378:metabolism*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D056189:Viral Tropism; D053585:Virus Attachment
chemical_list: D036022:Capsid Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011991:Receptors, Virus; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C062481:VP1 protein, polyomavirus; C070576:PML protein, human