1887

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. 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, 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 with the prototype JCV, the PML isolate JCV and the prototype JCV engineered with the GCN1-deletion. While all strains replicated at low levels in the medulloblastoma cell line DAOY from a cerebellar neuronal tumour, JCV replicated better in astroglial SVG cells than JCV or JCV 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 is replication-competent . 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.

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2012-01-01
2019-10-16
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References

  1. Arthur R. R. , Dagostin S. , Shah K. V. . ( 1989; ). Detection of BK virus and JC virus in urine and brain tissue by the polymerase chain reaction. . J Clin Microbiol 27:, 1174–1179.[PubMed]
    [Google Scholar]
  2. Berger J. R. , Kaszovitz B. , Post M. J. , Dickinson G. . ( 1987; ). Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. . Ann Intern Med 107:, 78–87.[PubMed] [CrossRef]
    [Google Scholar]
  3. Bilcock D. T. , Daniels L. E. , Bath A. J. , Halford S. E. . ( 1999; ). Reactions of type II restriction endonucleases with 8-base pair recognition sites. . J Biol Chem 274:, 36379–36386. [CrossRef] [PubMed]
    [Google Scholar]
  4. Bustamante F. , Luis Cartier R. , Manuel Lavados M. . ( 2009; ). Atrofia cerebelosa por el virus JC en un paciente con SIDA. . Rev Chin Neurro-Psiquiat 47:, 222–227.
    [Google Scholar]
  5. Carson K. R. , Evens A. M. , Richey E. A. , Habermann T. M. , Focosi D. , Seymour J. F. , Laubach J. , Bawn S. D. , Gordon L. I. . & other authors ( 2009; ). Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. . Blood 113:, 4834–4840. [CrossRef] [PubMed]
    [Google Scholar]
  6. Clifford D. B. , De Luca A. , Simpson D. M. , Arendt G. , Giovannoni G. , Nath A. . ( 2010; ). Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. . Lancet Neurol 9:, 438–446. [CrossRef] [PubMed]
    [Google Scholar]
  7. Dang X. , Koralnik I. J. . ( 2006; ). A granule cell neuron-associated JC virus variant has a unique deletion in the VP1 gene. . J Gen Virol 87:, 2533–2537. [CrossRef] [PubMed]
    [Google Scholar]
  8. Du Pasquier R. A. , Corey S. , Margolin D. H. , Williams K. , Pfister L. A. , De Girolami U. , Mac Key J. J. , Wüthrich C. , Joseph J. T. , Koralnik I. J. . ( 2003; ). Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. . Neurology 61:, 775–782.[PubMed] [CrossRef]
    [Google Scholar]
  9. Gorelik L. , Reid C. , Testa M. , Brickelmaier M. , Bossolasco S. , Pazzi A. , Bestetti A. , Carmillo P. , Wilson E. . & other authors ( 2011; ). Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. . J Infect Dis 204:, 103–114. [CrossRef] [PubMed]
    [Google Scholar]
  10. Granot R. , Lawrence R. , Barnett M. , Masters L. , Rodriguez M. , Theocharous C. , Pamphlett R. , Hersch M. . ( 2009; ). What lies beneath the tent? JC-virus cerebellar granule cell neuronopathy complicating sarcoidosis. . J Clin Neurosci 16:, 1091–1092. [CrossRef] [PubMed]
    [Google Scholar]
  11. Hacioglu E. , Basim H. , Stall R. E. . ( 1997; ). Optimized conditions of PacI and SwaI for genomic analysis of X. axonopodis pv. vesicatoria by PFGE. . Biotechniques 22:, 1026–1028.[PubMed]
    [Google Scholar]
  12. Hecht J. H. , Glenn O. A. , Wara D. W. , Wu Y. W. . ( 2007; ). JC virus granule cell neuronopathy in a child with CD40 ligand deficiency. . Pediatr Neurol 36:, 186–189. [CrossRef] [PubMed]
    [Google Scholar]
  13. Kitamura T. , Aso Y. , Kuniyoshi N. , Hara K. , Yogo Y. . ( 1990; ). High incidence of urinary JC virus excretion in nonimmunosuppressed older patients. . J Infect Dis 161:, 1128–1133. [CrossRef] [PubMed]
    [Google Scholar]
  14. Knowles W. A. , Pipkin P. , Andrews N. , Vyse A. , Minor P. , Brown D. W. , Miller E. . ( 2003; ). Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. . J Med Virol 71:, 115–123. [CrossRef] [PubMed]
    [Google Scholar]
  15. Koralnik I. J. , Boden D. , Mai V. X. , Lord C. I. , Letvin N. L. . ( 1999; ). JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. . Neurology 52:, 253–260.[PubMed] [CrossRef]
    [Google Scholar]
  16. Koralnik I. J. , Wüthrich C. , Dang X. , Rottnek M. , Gurtman A. , Simpson D. , Morgello S. . ( 2005; ). JC virus granule cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. . Ann Neurol 57:, 576–580. [CrossRef] [PubMed]
    [Google Scholar]
  17. Korman B. D. , Tyler K. L. , Korman N. J. . ( 2009; ). Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression: a cautionary tale for dermatologists. . Arch Dermatol 145:, 937–942. [CrossRef] [PubMed]
    [Google Scholar]
  18. Markowitz R. B. , Thompson H. C. , Mueller J. F. , Cohen J. A. , Dynan W. S. . ( 1993; ). Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects. . J Infect Dis 167:, 13–20. [CrossRef] [PubMed]
    [Google Scholar]
  19. Miller J. R. , Barrett R. E. , Britton C. B. , Tapper M. L. , Bahr G. S. , Bruno P. J. , Marquardt M. D. , Hays A. P. , McMurtry J. G. III . & other authors ( 1982; ). Progressive multifocal leukoencephalopathy in a male homosexual with T-cell immune deficiency. . N Engl J Med 307:, 1436–1438. [CrossRef] [PubMed]
    [Google Scholar]
  20. Neu U. , Maginnis M. S. , Palma A. S. , Ströh L. J. , Nelson C. D. , Feizi T. , Atwood W. J. , Stehle T. . ( 2010; ). Structure-function analysis of the human JC polyomavirus establishes the LSTc pentasaccharide as a functional receptor motif. . Cell Host Microbe 8:, 309–319. [CrossRef] [PubMed]
    [Google Scholar]
  21. Otis C. N. , Moral L. A. . ( 2005; ). Images in pathology: granule cell loss in AIDS-associated progressive multifocal leukoencephalopathy. . Int J Surg Pathol 13:, 360. [CrossRef] [PubMed]
    [Google Scholar]
  22. Schwab N. J. C. U. , Fox R. J. , Huang Y. H. , Schneider-Hohendorf T. , Stenner M.-P , Welch W. , Kieseier B. C , Monoranu C. M. , Staugaitis S. M. . & other authors ( 2009; ). Fatal progressive multifocal leukoencephalopathy associated with efalizumab therapy: insights into the role of leukointegrin aLb2 in JC virus control. . Multiple Sclerosis Journal 15:, 271–277.[CrossRef]
    [Google Scholar]
  23. Shimizu N. , Imamura A. , Daimaru O. , Mihara H. , Kato Y. , Kato R. , Oguri T. , Fukada M. , Yokochi T. . & other authors ( 1999; ). Distribution of JC virus DNA in peripheral blood lymphocytes of hematological disease cases. . Intern Med 38:, 932–937. [CrossRef] [PubMed]
    [Google Scholar]
  24. Shin H. W. , Kang S. Y. , Sohn Y. H. . ( 2008; ). JC viral infection-related cerebellar degeneration as the first manifestation of AIDS. . Eur Neurol 59:, 205–207. [CrossRef] [PubMed]
    [Google Scholar]
  25. Stehle T. , Gamblin S. J. , Yan Y. , Harrison S. C. . ( 1996; ). The structure of simian virus 40 refined at 3.1 Å resolution. . Structure 4:, 165–182. [CrossRef] [PubMed]
    [Google Scholar]
  26. Tagliati M. , Simpson D. , Morgello S. , Clifford D. , Schwartz R. L. , Berger J. R. . ( 1998; ). Cerebellar degeneration associated with human immunodeficiency virus infection. . Neurology 50:, 244–251.[PubMed] [CrossRef]
    [Google Scholar]
  27. Tan I. L. , Brew B. J. . ( 2009; ). Possible JCV granular cell neuronopathy in a patient with HIV infection. . Neurology 73:, 1598–1599. [CrossRef] [PubMed]
    [Google Scholar]
  28. Tan C. S. , Koralnik I. J. . ( 2010; ). Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. . Lancet Neurol 9:, 425–437. [CrossRef] [PubMed]
    [Google Scholar]
  29. Tan C. S. , Dezube B. J. , Bhargava P. , Autissier P. , Wüthrich C. , Miller J. , Koralnik I. J. . ( 2009; ). Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation. . J Infect Dis 199:, 881–888. [CrossRef] [PubMed]
    [Google Scholar]
  30. Tyler K. L. . ( 2003; ). The uninvited guest: JC virus infection of neurons in PML. . Neurology 61:, 734–735.[PubMed] [CrossRef]
    [Google Scholar]
  31. Weber T. , Trebst C. , Frye S. , Cinque P. , Vago L. , Sindic C. J. , Schulz-Schaeffer W. J. , Kretzschmar H. A. , Enzensberger W. . & other authors ( 1997; ). Analysis of the systemic and intrathecal humoral immune response in progressive multifocal leukoencephalopathy. . J Infect Dis 176:, 250–254. [CrossRef] [PubMed]
    [Google Scholar]
  32. Wüthrich C. , Dang X. , Westmoreland S. , McKay J. , Maheshwari A. , Anderson M. P. , Ropper A. H. , Viscidi R. P. , Koralnik I. J. . ( 2009; ). Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons. . Ann Neurol 65:, 742–748. [CrossRef] [PubMed]
    [Google Scholar]
  33. Yogo Y. , Kitamura T. , Sugimoto C. , Hara K. , Iida T. , Taguchi F. , Tajima A. , Kawabe K. , Aso Y. . ( 1991; ). Sequence rearrangement in JC virus DNAs molecularly cloned from immunosuppressed renal transplant patients. . J Virol 65:, 2422–2428.[PubMed]
    [Google Scholar]
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