Detection of viral DNA sequences in the cerebrospinal fluid of patients with multiple sclerosis

The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), in cerebrospinal fluid (C...

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Published inJournal of medical virology Vol. 82; no. 6; pp. 1051 - 1057
Main Authors Mancuso, Roberta, Hernis, Ambra, Cavarretta, Rosella, Caputo, Domenico, Calabrese, Elena, Nemni, Raffaello, Ferrante, Pasquale, Delbue, Serena, Clerici, Mario
Format Journal Article
LanguageEnglish
Published Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.05.2010
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Abstract The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), in cerebrospinal fluid (CSF) samples collected from 51 patients with MS and 30 patients with other neurological diseases. Cell-free or cell-associated viral DNA in CSF samples was detected by real-time PCR, and viral loads were determined. Magnetic resonance imaging (MRI) examinations were also performed to look for active lesions. Cell-associated JCV DNA was detected in 3 of the 51 patients with MS and in 2 of the 30 patients with other neurological disease. Cell-free JCV DNA was detected in one additional patient with MS. Cell-free VZV DNA was detected in one patient without MS, cell-free HHV-6 was detected in one patient with MS, and cell-free EBV was detected in one patient with MS. All other study patients had no detectable viral DNA in CSF samples and no double infections were found. The small percentage of patients with detectable viral DNA in CSF samples was comparable between patients with MS and those with other neurological disease, and presence of viral DNA was not a predictor of brain lesions. Additional observations suggest that cell trafficking from the periphery, rather than leakage through the blood-brain barrier, results in the transport of viruses to the CNS, where local immunosurveillance can control viral replication in immunocompetent individuals. J. Med. Virol. 82:1051-1057, 2010.
AbstractList The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), in cerebrospinal fluid (CSF) samples collected from 51 patients with MS and 30 patients with other neurological diseases. Cell-free or cell-associated viral DNA in CSF samples was detected by real-time PCR, and viral loads were determined. Magnetic resonance imaging (MRI) examinations were also performed to look for active lesions. Cell-associated JCV DNA was detected in 3 of the 51 patients with MS and in 2 of the 30 patients with other neurological disease. Cell-free JCV DNA was detected in one additional patient with MS. Cell-free VZV DNA was detected in one patient without MS, cell-free HHV-6 was detected in one patient with MS, and cell-free EBV was detected in one patient with MS. All other study patients had no detectable viral DNA in CSF samples and no double infections were found. The small percentage of patients with detectable viral DNA in CSF samples was comparable between patients with MS and those with other neurological disease, and presence of viral DNA was not a predictor of brain lesions. Additional observations suggest that cell trafficking from the periphery, rather than leakage through the blood-brain barrier, results in the transport of viruses to the CNS, where local immunosurveillance can control viral replication in immunocompetent individuals.The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), in cerebrospinal fluid (CSF) samples collected from 51 patients with MS and 30 patients with other neurological diseases. Cell-free or cell-associated viral DNA in CSF samples was detected by real-time PCR, and viral loads were determined. Magnetic resonance imaging (MRI) examinations were also performed to look for active lesions. Cell-associated JCV DNA was detected in 3 of the 51 patients with MS and in 2 of the 30 patients with other neurological disease. Cell-free JCV DNA was detected in one additional patient with MS. Cell-free VZV DNA was detected in one patient without MS, cell-free HHV-6 was detected in one patient with MS, and cell-free EBV was detected in one patient with MS. All other study patients had no detectable viral DNA in CSF samples and no double infections were found. The small percentage of patients with detectable viral DNA in CSF samples was comparable between patients with MS and those with other neurological disease, and presence of viral DNA was not a predictor of brain lesions. Additional observations suggest that cell trafficking from the periphery, rather than leakage through the blood-brain barrier, results in the transport of viruses to the CNS, where local immunosurveillance can control viral replication in immunocompetent individuals.
The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), in cerebrospinal fluid (CSF) samples collected from 51 patients with MS and 30 patients with other neurological diseases. Cell-free or cell-associated viral DNA in CSF samples was detected by real-time PCR, and viral loads were determined. Magnetic resonance imaging (MRI) examinations were also performed to look for active lesions. Cell-associated JCV DNA was detected in 3 of the 51 patients with MS and in 2 of the 30 patients with other neurological disease. Cell-free JCV DNA was detected in one additional patient with MS. Cell-free VZV DNA was detected in one patient without MS, cell-free HHV-6 was detected in one patient with MS, and cell-free EBV was detected in one patient with MS. All other study patients had no detectable viral DNA in CSF samples and no double infections were found. The small percentage of patients with detectable viral DNA in CSF samples was comparable between patients with MS and those with other neurological disease, and presence of viral DNA was not a predictor of brain lesions. Additional observations suggest that cell trafficking from the periphery, rather than leakage through the blood-brain barrier, results in the transport of viruses to the CNS, where local immunosurveillance can control viral replication in immunocompetent individuals. J. Med. Virol. 82:1051-1057, 2010.
The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV‐6), and Epstein‐Barr virus (EBV), in cerebrospinal fluid (CSF) samples collected from 51 patients with MS and 30 patients with other neurological diseases. Cell‐free or cell‐associated viral DNA in CSF samples was detected by real‐time PCR, and viral loads were determined. Magnetic resonance imaging (MRI) examinations were also performed to look for active lesions. Cell‐associated JCV DNA was detected in 3 of the 51 patients with MS and in 2 of the 30 patients with other neurological disease. Cell‐free JCV DNA was detected in one additional patient with MS. Cell‐free VZV DNA was detected in one patient without MS, cell‐free HHV‐6 was detected in one patient with MS, and cell‐free EBV was detected in one patient with MS. All other study patients had no detectable viral DNA in CSF samples and no double infections were found. The small percentage of patients with detectable viral DNA in CSF samples was comparable between patients with MS and those with other neurological disease, and presence of viral DNA was not a predictor of brain lesions. Additional observations suggest that cell trafficking from the periphery, rather than leakage through the blood–brain barrier, results in the transport of viruses to the CNS, where local immunosurveillance can control viral replication in immunocompetent individuals. J. Med. Virol. 82:1051–1057, 2010. © 2010 Wiley‐Liss, Inc.
The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought, including JC virus (JCV), varicella zoster virus (VZV), human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), in cerebrospinal fluid (CSF) samples collected from 51 patients with MS and 30 patients with other neurological diseases. Cell-free or cell-associated viral DNA in CSF samples was detected by real-time PCR, and viral loads were determined. Magnetic resonance imaging (MRI) examinations were also performed to look for active lesions. Cell-associated JCV DNA was detected in 3 of the 51 patients with MS and in 2 of the 30 patients with other neurological disease. Cell-free JCV DNA was detected in one additional patient with MS. Cell-free VZV DNA was detected in one patient without MS, cell-free HHV-6 was detected in one patient with MS, and cell-free EBV was detected in one patient with MS. All other study patients had no detectable viral DNA in CSF samples and no double infections were found. The small percentage of patients with detectable viral DNA in CSF samples was comparable between patients with MS and those with other neurological disease, and presence of viral DNA was not a predictor of brain lesions. Additional observations suggest that cell trafficking from the periphery, rather than leakage through the blood-brain barrier, results in the transport of viruses to the CNS, where local immunosurveillance can control viral replication in immunocompetent individuals.
Author Nemni, Raffaello
Calabrese, Elena
Ferrante, Pasquale
Mancuso, Roberta
Delbue, Serena
Cavarretta, Rosella
Caputo, Domenico
Hernis, Ambra
Clerici, Mario
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Issue 6
Keywords Gammaherpesvirinae
Human
Nervous system diseases
Multiple sclerosis
Nucleotide sequence
Herpesviridae
HHV-6
Epstein Barr virus
Cerebrospinal fluid
Inflammatory disease
Virus
VZV
Central nervous system disease
EBV
Detection
Human herpesvirus 6
JCV
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Delbue S, Sotgiu G, Fumagalli D, Valli M, Borghi E, Mancuso R, Marchioni E, Maserati R, Ferrante P. 2005. A case of a PML patient with four different JC virus TCR rearrangements in CSF, blood, serum and urine. J Neurovirol 11: 51-57.
Goodman AD, Mock DJ, Powers JM, Baker JV, Blumberg BM. 2003. Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions. J Infect Dis 187: 1365-1376.
Yao K, Gagnon S, Akhyani N, Williams E, Fotheringham J, Frohman E, Stuve O, Monson N, Racke MK, Jacobson S. 2008. Reactivation of human herpesvirus-6 in natalizumab treated multiple sclerosis patients. PLoS ONE 3: e2028.
Knox KK, Harrington DP, Carrigan DR. 1995. Fulminant human herpesvirus six encephalitis in a human immunodeficiency virus-infected infant. J Med Virol 45: 288-292.
Thacker EL, Mirzaei F, Ascherio A. 2006. Infectious mononucleosis and risk for multiple sclerosis: A meta-analysis. Ann Neurol 59: 499-503.
Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. 2005. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353: 375-381.
Caserta MT, Hall CB, Schnabel K, McIntyre K, Long C, Costanzo M, Dewhurst S, Insel R, Epstein LG. 1994. Neuroinvasion and persistence of human herpesvirus 6 in children. J Infect Dis 170: 1586-1589.
Alvarez-Lafuente R, García-Montojo M, De Las Heras V, Domínguez-Mozo MI, Bartolome M, Benito-Martin MS, Arroyo R. 2008. Herpesviruses and human endogenous retroviral sequences in the cerebrospinal fluid of multiple sclerosis patients. Mult Scler 14: 595-601.
Mancuso R, Delbue S, Borghi E, Pagani E, Calvo MG, Caputo D, Granieri E, Ferrante P. 2007. Increased prevalence of varicella zoster virus DNA in cerebrospinal fluid from patients with multiple sclerosis. J Med Virol 79: 192-199.
Opsahl ML, Kennedy PG. 2005. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain 128: 516-527.
Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW, SENTINEL Investigators. 2006. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354: 911-923.
Franciotta D, Avolio C, Capello E, Lolli F, AINI. 2005. Consensus recommendations of the Italian Association for Neuroimmunology for immunochemical cerebrospinal fluid examination. J Neurol Sci 237: 5-11.
Kuusisto H, Hyöty H, Kares S, Kinnunen E, Elovaara I. 2008. Human herpesvirus 6 and multiple sclerosis: A Finnish twin study. Mult Scler 14: 54-58.
Torkildsen Ø, Nyland H, Myrmel H, Myhr KM. 2008. Epstein-Barr virus reactivation and multiple sclerosis. Eur J Neurol 15: 106-108.
Focosi D, Kast RE, Maggi F, Ceccherini-Nelli L, Petrini M. 2009. JC virus DNA in healthy brain tissue: A challenge for progressive multifocal leukoencephalopathy diagnosis. Ann Neurol 65: 230.
Sugaya N, Yoshikawa T, Miura M, Ishizuka T, Kawakami C, Asano Y. 2002. Influenza encephalopathy associated with infection with human herpesvirus 6 and/or human herpesvirus 7. Clin Infect Dis 34: 461-466.
Buljevac D, van Doornum GJ, Flach HZ, Groen J, Osterhaus AD, Hop W, van Doorn PA, van der Meché FG, Hintzen RQ. 2005. Epstein-Barr virus and disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 76: 1377-1381.
Iacobaeus E, Ryschkewitsch C, Gravell M, Khademi M, Wallstrom E, Olsson T, Brundin L, Major E. 2008. Analysis of cerebrospinal fluid and cerebrospinal fluid cells from patients with multiple sclerosis for detection of JC virus DNA. Mult Scler 15: 28-35.
McFarland HF, Jacobson S. 2006. Natalizumab and immune cells. Arch Neurol 63: 1366-1367.
Alvarez-Lafuente R, García-Montojo M, De Las Heras V, Bartolomé M, Arroyo R. 2007. JC virus in cerebrospinal fluid samples of multiple sclerosis patients at the first demyelinating event. Mult Scler 13: 590-595.
Mori M, Kurata H, Tajima M, Shimada H. 1991. JC virus detection by in situ hybridization in brain tissue from elderly patients. Ann Neurol 29: 428-432.
Eggers C, Stellbrink HJ, Buhk T, Dörries K. 1999. Quantification of JC virus DNA in the cerebrospinal fluid of patients with human immunodeficiency virus-associated progressive multifocal leukoencephalopathy-A longitudinal study. J Infect Dis 180: 1690-1694.
Ordoñez G, Pineda B, Garcia-Navarrete R, Sotelo J. 2004. Brief presence of varicella-zoster viral DNA in mononuclear cells during relapses of multiple sclerosis. Arch Neurol 61: 529-532.
Stoner GL. 1991. Implications of progressive multifocal leukoencephalopathy and JC virus for the etiology of MS. Acta Neurol Scand 83: 20-33.
Stüve O, Marra CM, Bar-Or A, Niino M, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Jerome KR, Cook L, Grand'Maison F, Hemmer B, Monson NL, Racke MK. 2006. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 63: 1383-1387.
Bossolasco S, Marenzi R, Dahl H, Vago L, Terreni MR, Broccolo F, Lazzarin A, Linde A, Cinque P. 1999. Human herpesvirus 6 in cerebrospinal fluid of patients infected with HIV: Frequency and clinical significance. J Neurol Neurosurg Psychiatry 67: 789-792.
Kleinschmidt-DeMasters BK, Tyler KL. 2005. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353: 369-374.
Borghi E, Pagani E, Mancuso R, Delbue S, Valli M, Mazziotti R, Giordano L, Micheli R, Ferrante P. 2005. Detection of herpesvirus-6A in a case of subacute cerebellitis and myoclonic dystonia. J Med Virol 75: 427-429.
Bogdanovic G, Priftakis P, Hammarin AL, Söderström M, Samuelson A, Lewensohn-Fuchs I, Dalianis T. 1998. Detection of JC virus in cerebrospinal fluid (CSF) samples from patients with progressive multifocal leukoencephalopathy but not in CSF samples from patients with herpes simplex encephalitis, enteroviral meningitis, or multiple sclerosis. J Clin Microbiol 36: 1137-1138.
Yoshikawa T, Ihira M, Suzuki K, Suga S, Matsubara T, Furukawa S, Asano Y. 2000. Invasion by human herpesvirus 6 and human herpesvirus 7 of the central nervous system in patients with neurological signs and symptoms. Arch Dis Child 83: 170-171.
Khalili K, White MK, Lublin F, Ferrante P, Berger JR. 2007. Reactivation of JC virus and development of PML in patients with multiple sclerosis. Neurology 68: 985-990.
Studahl M, Hagberg L, Rekabdar E, Bergström T. 2000. Herpesvirus DNA detection in cerebral spinal fluid: Differences in clinical presentation between alpha-, beta-, and gamma-herpesviruses. Scand J Infect Dis 32: 237-248.
Sweet TM, Del Valle L, Khalili K. 2002. Molecular biology and immunoregulation of human neurotropic JC virus in CNS. J Cell Physiol 191: 249-256.
Sotelo J. 2007. On the viral hypothesis of multiple sclerosis: Participation of varicella-zoster virus. J Neurol Sci 262: 113-116.
Delbue S, Branchetti E, Boldorini R, Vago L, Zerbi P, Veggiani C, Tremolada S, Ferrante P. 2008. Presence and expression of JCV early gene large T antigen in the brains of immunocompromised and immunocompetent individuals. J Med Virol 80: 2147-2152.
Calabrese LH, Molloy ES, Huang D, Ransohoff RM. 2007. Progressive multifocal leukoencephalopathy in rheumatic diseases: Evolving clinical and pathologic patterns of disease. Arthritis Rheum 56: 2116-2128.
Behzad-Behbahani A, Klapper PE, Vallely PJ, Cleator GM, Khoo SH. 2004. Detection of BK virus and JC virus DNA in urine samples from immunocompromised (HIV-infected) and immunocompetent (HIV-non-infected) patients using polymerase chain reaction and microplate hybridisation. J Clin Virol 29: 224-229.
Elsner C, Dörries K. 1992. Evidence of human polyomavirus BK and JC infection in normal brain tissue. Virology 191: 72-80.
Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F. 2007. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 204: 2899-2912.
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Snippet The role of viruses in the pathogenesis of multiple sclerosis (MS) is a subject of heated debate. The presence of six different neurotropic viruses was sought,...
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SubjectTerms Adolescent
Adult
Aged
Aged, 80 and over
Biological and medical sciences
cerebrospinal fluid
Cerebrospinal Fluid - virology
DNA, Viral - genetics
DNA, Viral - isolation & purification
EBV
Female
Fundamental and applied biological sciences. Psychology
Herpesvirus 3, Human - genetics
Herpesvirus 4, Human - genetics
Herpesvirus 6, Human - genetics
HHV-6
Human viral diseases
Humans
Infectious diseases
JC Virus - genetics
JCV
Male
Medical sciences
Microbiology
Middle Aged
Miscellaneous
multiple sclerosis
Multiple Sclerosis - virology
Viral diseases
Virology
VZV
Young Adult
Title Detection of viral DNA sequences in the cerebrospinal fluid of patients with multiple sclerosis
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https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fjmv.21764
https://www.ncbi.nlm.nih.gov/pubmed/20419821
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https://www.proquest.com/docview/742692978
Volume 82
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