1887

Abstract

Multiple sclerosis (MS)-associated retrovirus (MSRV)/HERV-W (human endogenous retrovirus W) and (HHV-6) are the two most studied (and discussed) viruses as environmental co-factors that trigger MS immunopathological phenomena. Autopsied brain tissues from MS patients and controls and peripheral blood mononuclear cells (PBMCs) were analysed. Quantitative RT-PCR and PCR with primers specific for MSRV/HERV-W and and HHV-6 U94/ and were used to determine virus copy numbers. Brain sections were immunostained with HERV-W env-specific monoclonal antibody to detect the viral protein. All brains expressed MSRV/HERV-W and genes. Phylogenetic analysis indicated that cerebral MSRV/HERV-W-related sequences, plasmatic MSRV, HERV-W and ERVWE1 (syncytin) are related closely. Accumulation of MSRV/HERV-W-specific RNAs was significantly greater in MS brains than in controls (=0.014 vs healthy controls; =0.006 vs pathological controls). By immunohistochemistry, no HERV-W env protein was detected in control brains, whereas it was upregulated within MS plaques and correlated with the extent of active demyelination and inflammation. No HHV-6-specific RNAs were detected in brains of MS patients; one healthy control had latent HHV-6 and one pathological control had replicating HHV-6. At the PBMC level, all MS patients expressed MSRV/HERV-W at higher copy numbers than did controls (=0.00003). Similar HHV-6 presence was found in MS patients and healthy individuals; only one MS patient had replicating HHV-6. This report, the first to study both MSRV/HERV-W and HHV-6, indicates that MSRV/HERV-W is expressed actively in human brain and activated strongly in MS patients, whilst there are no significant differences between these MS patients and controls for HHV-6 presence/replication at the brain or PBMC level.

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2007-01-01
2024-03-28
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References

  1. Alvarez-Lafuente R., De las Heras V., Bartolome M., Picazo J. J., Arroyo R. 2004; Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection. Arch Neurol 61:1523–1527 [CrossRef]
    [Google Scholar]
  2. Antony J. M., Van Marle G., Opii W., Butterfield D. A., Mallet F., Yong V. W., Wallace J. L., Deacon R. M., Warren K., Power C. 2004; Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci 7:1088–1095 [CrossRef]
    [Google Scholar]
  3. Blaise S., de Parseval N., Benit L., Heidmann T. 2003; Genomewide screening for fusogenic human endogenous retrovirus envelopes identifies syncytin 2, a gene conserved on primate evolution. Proc Natl Acad Sci U S A 100:13013–13018 [CrossRef]
    [Google Scholar]
  4. Blond J. L., Beseme F., Duret L., Bouton O., Bedin F., Perron H., Mandrand B., Mallet F. 1999; Molecular characterisation and placental expression of HERV-W, a new human endogenous retrovirus family. J Virol 73:1175–1185
    [Google Scholar]
  5. Blond J. L., Lavillette D., Cheynet V., Bouton O., Oriol G., Chapel-Fernandes S., Mandrand B., Mallet F., Cosset F. L. 2000; An envelope glycoprotein of the human endogenous retrovirus HERV-W is expressed in the human placenta and fuses cells expressing the type D mammalian retrovirus receptor. J Virol 74:3321–3329 [CrossRef]
    [Google Scholar]
  6. Bonetti B., Valdo P., Ossi G., De Toni L., Masotto B., Marconi S., Rizzuto N., Nardelli E., Moretto G. 2003; T-cell cytotoxicity of human Schwann cells: TNFalpha promotes fasL-mediated apoptosis and IFN gamma perforin-mediated lysis. Glia 43:141–148 [CrossRef]
    [Google Scholar]
  7. Brudek T., Christensen T., Hansen H. J., Bobecka J., Moller-Larsen A. 2004; Simultaneous presence of endogenous retrovirus and herpes virus antigens has profound effect on cell-mediated immune responses: implications for multiple sclerosis. AIDS Res Hum Retroviruses 20:415–423 [CrossRef]
    [Google Scholar]
  8. Cermelli C., Berti R., Soldan S. S., Mayne M., D'ambrosia J. M., Ludwin S. K., Jacobson S. 2003; High frequency of human herpesvirus 6 DNA in multiple sclerosis plaques isolated by laser microdissection. J Infect Dis 187:1377–1387 [CrossRef]
    [Google Scholar]
  9. Christensen T. 2005; Association of human endogenous retroviruses with multiple sclerosis and possible interactions with herpes viruses. Rev Med Virol 15:179–211 [CrossRef]
    [Google Scholar]
  10. Christensen T. 2006; The role of EBV in MS pathogenesis. Int MS J 13:52–57
    [Google Scholar]
  11. Clark D. 2004; Human herpesvirus type 6 and multiple sclerosis. Herpes 11 (Suppl. 2):112A–119A
    [Google Scholar]
  12. Delorenze G. N., Munger K. L., Lennette E. T., Orentreich N., Vogelman J. H., Ascherio A. 2006; Epstein-Barr virus and multiple sclerosis: evidence of association from a prospective study with long-term follow-up. Arch Neurol 63:839–844 [CrossRef]
    [Google Scholar]
  13. Dolei A. 2005; MSRV/HERV-W/syncytin and its linkage to multiple sclerosis: the usability and the hazard of a human endogenous retrovirus. J Neurovirol 11:232–235 [CrossRef]
    [Google Scholar]
  14. Dolei A. 2006; Endogenous retroviruses and human disease. Expert Rev Clin Immunol 2:149–167 [CrossRef]
    [Google Scholar]
  15. Dolei A., Serra C., Mameli G., Pugliatti M., Sechi S., Cirotto M. C., Rosati G., Sotgiu S. 2002; Multiple sclerosis-associated retrovirus (MSRV) in Sardinian MS patients. Neurology 58:471–473 [CrossRef]
    [Google Scholar]
  16. Donati D., Akhyani N., Fogdell-Hahn A., Cermelli C., Cassiani-Ingoni R., Vortmeyer A., Heiss J. D., Cogen P., Gaillard W. D. other authors 2003; Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 61:1405–1411 [CrossRef]
    [Google Scholar]
  17. Firouzi R., Rolland A., Michel M., Jouvin-Marche E., Hauw J. J., Malcus-Vocanson C., Lazarini F., Gebuhrer L., Seigneurin J. M. other authors 2003; Multiple sclerosis-associated retrovirus particles cause T lymphocyte-dependent death with brain hemorrhage in humanized SCID mice model. J Neurovirol 9:79–93 [CrossRef]
    [Google Scholar]
  18. Forsman A., Yun Z., Hu L., Uzhameckis D., Jern P., Blomberg J. 2005; Development of broadly targeted human endogenous gammaretroviral pol-based real time PCRs quantitation of RNA expression in human tissues. J Virol Methods 129:16–30 [CrossRef]
    [Google Scholar]
  19. Fotheringham J., Jacobson S. 2005; Human herpesvirus 6 and multiple sclerosis: potential mechanisms for virus-induced disease. Herpes 12:4–9
    [Google Scholar]
  20. Garson J. A., Tuke P. W., Giraud P., Paranhos-Baccala G., Perron H. 1998; Detection of virion-associated MSRV-RNA in serum of patients with multiple sclerosis. Lancet 351:33 [CrossRef]
    [Google Scholar]
  21. Garson J., Créange A., Dolei A., Ferrante P., Jouvin-Marche E., Marche P. N., Rieger F., Ruprecht K., Saresella M. other authors 2005; MSRV, syncytin and the role of endogenous retroviral proteins in demyelination. Mult Scler 11:249–250 [CrossRef]
    [Google Scholar]
  22. Goodman A. D., Mock D. J., Powers J. M., Baker J. V., Blumberg B. M. 2003; Human herpesvirus 6 genome and antigen in acute multiple sclerosis lesions. J Infect Dis 187:1365–1376 [CrossRef]
    [Google Scholar]
  23. Griscelli F., Barrois M., Chauvin S., Lastere S., Bellet D., Bourhis J. H. 2001; Quantification of human cytomegalovirus DNA in bone marrow transplant recipients by real-time PCR. J Clin Microbiol 39:4362–4369 [CrossRef]
    [Google Scholar]
  24. Hollsberg P., Kusk M., Bech E., Hansen H. J., Jakobsen J., Haahr S. 2005; Presence of Epstein-Barr virus and human herpesvirus 6B DNA in multiple sclerosis patients: associations with disease activity. Acta Neurol Scand 112:395–402 [CrossRef]
    [Google Scholar]
  25. Johnston J. B., Silva C., Holden J., Warren K. G., Clark A. W., Power C. 2001; Monocyte activation and differentiation augment human endogenous retrovirus expression: implications for inflammatory brain diseases. Ann Neurol 50:434–442 [CrossRef]
    [Google Scholar]
  26. Karlsson H., Schröder J., Bachmann S., Bottmer C., Yolken R. H. 2004; HERV-W-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder. Mol Psychiatry 9:12–13 [CrossRef]
    [Google Scholar]
  27. Komurian-Pradel F., Paranhos-Baccala G., Bedin F., Ounanian-Paraz A., Sodoyer M., Ott C., Rajoharison A., Garcia E., Mallet F., Mandrand B., Perron H. other authors 1999; Molecular cloning and characterization of MSRV-related sequences associated with retrovirus-like particles. Virology 260:1–9 [CrossRef]
    [Google Scholar]
  28. Kwok S., Higuchi R. 1989; Avoiding false positives with PCR. Nature 339:237–238 [CrossRef]
    [Google Scholar]
  29. Lafon M., Jouvin-Marche E., Marche P. N., Perron H. 2002; Human viral superantigens: to be or not to be transactivated?. Trends Immunol 23:238–239 [CrossRef]
    [Google Scholar]
  30. Lolli F., Mulinacci B., Carotenuto A., Bonetti B., Sabatino G., Mazzanti B., D'Ursi A. M., Novellino E., Pazzagli M. other authors 2005; An N-glucosylated peptide detecting disease-specific autoantibodies, biomarkers of multiple sclerosis. Proc Natl Acad Sci U S A 102:10273–10278 [CrossRef]
    [Google Scholar]
  31. Menard A., Amouri R., Michel M., Marcel F., Brouillet A., Belliveau J., Geny C., Deforges L., Malcus-Vocanson C. other authors 1997; Gliotoxicity, reverse transcriptase activity and retroviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis. FEBS Lett 413:477–485 [CrossRef]
    [Google Scholar]
  32. Mi S., Lee X., Li X., Veldman G. M., Finnerty H., Racie L., LaVallie E., Tang X. Y., Edouard P. other authors 2000; Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403:785–789 [CrossRef]
    [Google Scholar]
  33. Moore F. G. A., Wolfson C. 2002; Human herpes virus 6 and multiple sclerosis. Acta Neurol Scand 106:63–83 [CrossRef]
    [Google Scholar]
  34. Muir A., Lever A., Moffett A. 2004; Expression and functions of human endogenous retroviruses in the placenta: an update. Placenta 25 (Suppl. 1):S16–S25 [CrossRef]
    [Google Scholar]
  35. Noseworthy J. H., Lucchinetti C., Rodriguez M., Weinshenker B. G. 2000; Multiple sclerosis. N Engl J Med 343:938–952 [CrossRef]
    [Google Scholar]
  36. Nowak J., Januszkiewicz D., Pernak M., Liwen I., Zawada M., Rembowska J., Nowicka K., Lewandowski K., Hertmanowska H., Wender M. 2003; Multiple sclerosis-associated virus-related pol sequences found both in multiple sclerosis and healthy donors are more frequently expressed in multiple sclerosis patients. J Neurovirol 9:112–117 [CrossRef]
    [Google Scholar]
  37. Opsahl M. L., Kennedy P. G. 2005; Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain 128:516–527 [CrossRef]
    [Google Scholar]
  38. Perron H., Geny C., Laurent A., Mouriquand C., Pellat J., Perret J., Seigneurin J. M. 1989; Leptomeningeal cell line from multiple sclerosis with reverse transcriptase activity and viral particles. Res Virol 140:551–561 [CrossRef]
    [Google Scholar]
  39. Perron H., Suh M., Lalande B., Gratacap B., Laurent A., Stoebner P., Seigneurin J. M. 1993; Herpes simplex virus ICP0 and ICP4 immediate early proteins strongly enhance expression of a retrovirus harboured by a leptomeningeal cell line from a patient with multiple sclerosis. J Gen Virol 74:65–72 [CrossRef]
    [Google Scholar]
  40. Perron H., Firouzi R., Tuke P., Garson J. A., Michel M., Beseme F., Bedin F., Mallet F., Marcel E. & other authors (1997a). Cell cultures and associated retroviruses in multiple sclerosis. Collaborative Research Group on MS. Acta Neurol Scand Suppl 169:22–31
    [Google Scholar]
  41. Perron H., Garson J. A., Bedin F., Beseme F., Paranhos-Baccala G., Komurian-Pradel F., Mallet F., Tuke P. W., Voisset C. other authors 1997b; Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci U S A 94:7583–7588 [CrossRef]
    [Google Scholar]
  42. Perron H., Jouvin-Marche E., Michel M., Ounanian-Paraz A., Camelo S., Dumon A., Jolivet-Reynaud C., Marcel F., Souillet Y. other authors 2001; Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vbeta16 T-lymphocyte activation. Virology 287:321–332 [CrossRef]
    [Google Scholar]
  43. Perron H., Lazarini F., Ruprecht K., Pechoux-Longin C., Seilhean D., Sazdovitch V., Creange A., Battail-Poirot N., Sibai G. other authors 2005; Human endogenous retrovirus (HERV)-W ENV and GAG proteins: physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions. J Neurovirol 11:23–33
    [Google Scholar]
  44. Pfaffl M. W., Hageleit M. 2001; Validities of mRNA quantification using recombinant RNA and recombinant DNA external calibration curves in real-time RT-PCR. Biotechnol Lett 23:275–282 [CrossRef]
    [Google Scholar]
  45. Rotola A., Merlotti I., Caniatti L., Caselli E., Granieri E., Tola M. R., Di Luca D., Cassai E. 2004; Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease. Mult Scler 10:348–354 [CrossRef]
    [Google Scholar]
  46. Serra C., Sotgiu S., Mameli G., Pugliatti M., Rosati G., Dolei A. 2001; Multiple sclerosis and multiple sclerosis-associated retrovirus in Sardinia. Neurol Sci 22:171–173 [CrossRef]
    [Google Scholar]
  47. Serra C., Mameli G., Arru G., Sotgiu S., Rosati G., Dolei A. 2003; In vitro modulation of the multiple sclerosis (MS)-associated retrovirus by cytokines: implications for MS pathogenesis. J Neurovirol 9:637–643
    [Google Scholar]
  48. Sotgiu S., Pugliatti M., Sanna A., Sotgiu A., Castiglia P., Solinas G., Dolei A., Serra C., Bonetti B., Rosati G. 2002a; Multiple sclerosis complexity in selected populations: the challenge of Sardinia, insular Italy. Eur J Neurol 9:329–341 [CrossRef]
    [Google Scholar]
  49. Sotgiu S., Serra C., Mameli G., Pugliatti M., Rosati G., Arru G., Dolei A. 2002b; Multiple sclerosis-associated retrovirus and MS prognosis: an observational study. Neurology 59:1071–1073 [CrossRef]
    [Google Scholar]
  50. Sotgiu S., Arru G., Söderström M., Mameli G., Serra C., Dolei A. 2006; Multiple sclerosis-associated retrovirus and optic neuritis. Mult Scler 12:357–359 [CrossRef]
    [Google Scholar]
  51. Sotgiu S., Arru G., Mameli G., Serra C., Pugliatti M., Rosati G., Dolei A. 2007; MSRV in early multiple sclerosis: a six-year follow-up of a Sardinian cohort. Mult Scler (in press
    [Google Scholar]
  52. Thompson J. D., Gibson T. J., Plewniak F., Jeanmougin F., Higgins D. G. 1997; The clustal_x windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 25:4876–4882 [CrossRef]
    [Google Scholar]
  53. Tuke P. W., Hawke S., Griffiths P. D., Clark D. A. 2004; Distribution and quantification of human herpesvirus 6 in multiple sclerosis and control brains. Mult Scler 10:355–359 [CrossRef]
    [Google Scholar]
  54. Virtanen J. O., Zabriskie J. B., Siren V., Friedman J. E., Lyons M. J., Edgar M., Vaheri A., Koskiniemi M. 2005; Co-localization of human herpes virus 6 and tissue plasminogen activator in multiple sclerosis brain tissue. Med Sci Monit 11:BR84–BR87
    [Google Scholar]
  55. Yi J.-M., Kim H.-M., Kim H.-S. 2004; Expression of the human endogenous retrovirus HERV-W family in various human tissues and cancer cells. J Gen Virol 85:1203–1210 [CrossRef]
    [Google Scholar]
  56. Yoshikawa T., Asano Y., Akimoto S., Ozaki T., Iwasaki T., Kurata T., Goshima F., Nishiyama Y. 2002; Latent infection of human herpesvirus 6 in astrocytoma cell line and alteration of cytokine synthesis. J Med Virol 66:497–505 [CrossRef]
    [Google Scholar]
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