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. 2004 Oct 8;36(Suppl):S54–S60. doi: 10.1002/ana.410360715

The virology of demyelinating diseases

Richard T Johnson 1,
PMCID: PMC7159614  PMID: 8017889

Abstract

Infectious agents have been postulated as causes of multiple sclerosis for over a century. The possible role of a virus or viruses is supported by data that (1) a childhood exposure is involved and “viral” infections may precipitate exacerbations of disease, (2) experimental infections in animals and natural infections in humans can cause diseases with long incubation periods, remitting and relapsing courses, and demyelination, and (3) patients with multiple sclerosis have abnormal immune responses to viruses. The pathogenesis of three human demyelinating diseases of known viral etiology is discussed. In progressive multifocal leukoencephalopathy, a papovavirus selectively infects oligodendrocytes and causes focal areas of demyelination. In postmeasles encephalomyelitis, the virus is lymphotrophic and disrupts immune regulation that can result in an autoimmune perivenular demyelinating illness without evidence of infection of the central nervous system. In human immunodeficiency virus‐encephalopathy and myelopathy virus is present in macrophages and microglia and the myelin abnormalities apparently are caused by soluble factors such as viral proteins, cytokines, or neurotoxins. These findings may have implications on how, when, and where to seek viruses in multiple sclerosis.

References

  • 1. Marie P. Sclérose en plaques et maladies infectieuses. Prog Med 1884; 12: 287–289 [Google Scholar]
  • 2. Bebbe GW, Kurtzke JF, Kurland LT, et al. Studies on the natural history of multiple sclerosis. III. Epidemiologic analysis of the Army experience in World War II. Neurology 1967; 17: 1–17 [DOI] [PubMed] [Google Scholar]
  • 3. Dean G, Kurtzke JF. On the risk of multiple sclerosis according to age at immigration to South Africa. Br Med J 1971; 3: 725–729 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985; 2: 1313–1315 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Andersen O, Lygner P‐E, Bergström T, et al. Viral infections trigger multiple sclerosis relapses: a prospective seroepidemiological study. J Neurol 1993; 240: 417–422 [DOI] [PubMed] [Google Scholar]
  • 6. Horvath CJ, Simon MA, Bergsagel DJ, et al. Simian virus 40 (SV40)‐induced disease in rhesus monkeys with simian acquired immunodeficiency syndrome. Am J Pathol 1992; 140: 1431–1440 [PMC free article] [PubMed] [Google Scholar]
  • 7. Zurbriggen A, Yamawaki M, Vandevelde M. Restricted canine distemper virus infection of oligodendrocytes. Lab Invest 1993; 68: 277–284 [PubMed] [Google Scholar]
  • 8. Lai MMC, Stohlman SA. Molecular basis of neuropathogenicity of mouse hepatitis virus In: Roos RP, ed. Molecular neurovirology. Totowa, NJ: Humana, 1992: 319–348 [Google Scholar]
  • 9. Roos RP, Casteel N. Determinants of neurological disease induced by Theiler's murine encephalomyelitis virus In: Roos RP, ed. Molecular neurovirology. Totowa, NJ: Humana, 1992: 283–318 [Google Scholar]
  • 10. Skiram S, Topham DJ, Huang S‐K, et al. Treatment of encephalomyocarditis virus‐induced central nervous system demyelination with monoclonal anti‐T‐cell antibodies. J Virol 1989; 63: 4242–4248 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Fazakerley JK, Webb HE. Semliki forest virus‐induced, immune‐mediated demyelination: adoptive transfer studies and viral persistence in nude mice. J Gen Virol 1987; 68: 377–385 [DOI] [PubMed] [Google Scholar]
  • 12. Seay AR, Wolinsky JS. Ross river virus‐induced demyelination: I. Pathogenesis and histopathology. Ann Neurol 1982; 12: 380–389 [DOI] [PubMed] [Google Scholar]
  • 13. Del Canto MC, Rabinowitz SG, Johnson TC. Virus‐induced demyelination. Production by a viral temperature sensitive mutant. J Neurol Sci 1979; 42: 155–168 [DOI] [PubMed] [Google Scholar]
  • 14. Narayan O, Clements JE. Biology and pathogenesis of lentiviruses. J Gen Virol 1989; 70: 1617–1639 [DOI] [PubMed] [Google Scholar]
  • 15. Adams JM, Imagawa DT. Measles antibodies in multiple sclerosis. Proc Soc Exp Biol Med 1962; 111: 562–566 [DOI] [PubMed] [Google Scholar]
  • 16. Bray PF, Bloomer LC, Salmon VC, et al. Epstein‐Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch Neurol 1983; 40: 406–408 [DOI] [PubMed] [Google Scholar]
  • 17. Norrby E. Viral antibodies in multiple sclerosis. Prog Med Virol 1978; 24: 1–39 [PubMed] [Google Scholar]
  • 18. Salmi A, Reunanen M, Ilonen J, et al. Intrathecal antibody synthesis to virus antigens in multiple sclerosis. Clin Exp Immunol 1983; 52: 241–249 [PMC free article] [PubMed] [Google Scholar]
  • 19. Ohta M, Ohta K, Mori F, et al. Sera from patients with multiple sclerosis react with human T cell lymphotropic virus‐I gag proteins but not env proteins—western blotting analysis. J Immunol 1986; 137: 3440–3443 [PubMed] [Google Scholar]
  • 20. Goswami KKA, Randall RE, Lange LS, et al. Antibodies against the paramyxovirus SV5 in the cerebrospinal fluids of some multiple sclerosis patients. Nature 1987; 327: 244–247 [DOI] [PubMed] [Google Scholar]
  • 21. Astrom KE, Mancall EL, Richardson, EP Jr. Progressive multifocal leukoencephalopathy. Brain 1958; 81: 93–111 [DOI] [PubMed] [Google Scholar]
  • 22. Price RW, Nielsen S, Horten B, et al. Progressive multifocal leukoencephalopathy: a burnt‐out case. Ann Neurol 1983; 13: 485–490 [DOI] [PubMed] [Google Scholar]
  • 23. Berger JR, Mucke L. Prolonged survival and partial recovery in AIDS‐associated progressive multifocal leukoencephalopathy. Neurology 1988; 38: 1060–1065 [DOI] [PubMed] [Google Scholar]
  • 24. Richardson, EP Jr. Progressive multifocal leukoencephalopathy. N Engl J Med 1961; 265: 815–823 [DOI] [PubMed] [Google Scholar]
  • 25. ZuRhein GM, Chou SM. Particles resembling papovavirus in human cerebral demyelinating disease. Science 1965; 148: 1477–1479 [DOI] [PubMed] [Google Scholar]
  • 26. Padgett L, Walker DL, ZuRhein GM, et al. Cultivation of papova‐like virus from human brain with progressive multifocal leukoencephalopathy. Lancet 1971; 1: 1257 [DOI] [PubMed] [Google Scholar]
  • 27. Weiner LP, Narayan O, Penney, JB Jr , et al. Papovavirus of JC type in progressive multifocal leukoencephalopathy. Arch Neurol 1973; 29: 1–3 [DOI] [PubMed] [Google Scholar]
  • 28. Narayan O, Penney JB Jr, Johnson RT, et al. Etiology of progressive multifocal leukoencephalopathy‐identification of papovavirus. N Engl J Med 1973; 289: 1278–1282 [DOI] [PubMed] [Google Scholar]
  • 29. Aksamit AJ, Sever JL, Major EO. Progressive multifocal leukoencephalopathy: JC virus detection by in situ hybridization compared with immunohistochemistry. Neurology 1986; 36: 499–504 [DOI] [PubMed] [Google Scholar]
  • 30. Johnson RT, Weiner LP, Narayan O, et al. Progressive multifocal leukoencephalopathy In: ter Meulern V, Katz M, eds. Slow virus infections of the central nervous system. New York: Springer‐Verlag, 1977: 99–100 [Google Scholar]
  • 31. Johnson RT, Griffin DE, Gendelman HE. Postinfectious encephalomyelitis. Semin Neurol 1985; 5: 180–190 [Google Scholar]
  • 32. Johnson RT, Griffin DE. Postinfectious encephalomyelitis In: Kennedy PGE, Johnson RT, eds. Infections of the nervous system. London: Butterworths, 1987: 209–226 [Google Scholar]
  • 33. Gendelman HE. Pezeshkpour GH, Pressman NJ, et al. A quantitation of myelin‐associated glycoprotein and myelin basic protein loss in different demyelinating diseases. Ann Neurol 1985; 18: 324–328 [DOI] [PubMed] [Google Scholar]
  • 34. Asaad F. Measles: summary of worldwide impact. Rev Infect Dis 1983; 5: 452–459 [DOI] [PubMed] [Google Scholar]
  • 35. von Pirquet C. Das verhalten der kutanen tuberkulin‐reaktion wahrend der Masern. Dtsch Med Wochenschr 1908; 34: 1297–1300 [Google Scholar]
  • 36. Hirsh RL, Griffin DE, Johnson RT, et al. Cellular immune responses during complicated and uncomplicated measles virus infections of man. Clin Immunol Immunopathol 1984; 31: 1–12 [DOI] [PubMed] [Google Scholar]
  • 37. Griffin DE, Moench TR, Johnson RT, et al. Peripheral blood mononuclear cells during natural measles virus infection: cell surface phenotypes and evidence for activation. Clin Immunol Immunopathol 1986; 40: 305–312 [DOI] [PubMed] [Google Scholar]
  • 38. Tamashiro VG, Perez HH, Griffin DE. Prospective study of the magnitude and duration of changes in tuberculin reactivity during complicated and uncomplicated measles. Pediatr Infect Dis J 1987; 6: 451–454 [DOI] [PubMed] [Google Scholar]
  • 39. Graves M, Griffin DE, Johnson RT, et al. Development of antibody to measles virus polypeptides during complicated and uncomplicated measles virus infections. J Virol 1984; 49: 409–412 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Griffin DE, Ward BJ, Jauregui E, et al. Immune activation during measles. N Engl J Med 1989; 320: 1667–1672 [DOI] [PubMed] [Google Scholar]
  • 41. Ward BJ, Johnson RT, Vaisberg A, et al. Spontaneous proliferation of peripheral mononuclear cells in natural measles virus infection: identification of dividing cells and correlation with mitogen responsiveness. Clin Immunol Immunopathol 1990; 55: 315–326 [DOI] [PubMed] [Google Scholar]
  • 42. Griffin DE, Cooper SJ, Hirsch RL, et al. Changes in plasma IgE levels during complicated and uncomplicated measles virus infections. J Allergy Clin Immunol 1985; 76: 206–213 [DOI] [PubMed] [Google Scholar]
  • 43. Griffin DE, Hirsch RL, Johnson RT, et al. Changes in serum C‐reactive protein during complicated and uncomplicated measles virus infections. Infect Immun 1983; 41: 861–864 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Griffin DE, Ward BJ, Juaregui E, et al. Immune activation during measles. b̃‐2 microglobulin in plasma and cerebrospinal fluid in complicated disease. J Infect Dis 1992; 166: 1170–1173 [DOI] [PubMed] [Google Scholar]
  • 45. Ward BJ, Johnson RT, Vaisberg A, et al. Cytokine production in vitro and the lymphoproliferative defect of natural measles virus infection. Clin Immunol Immunopathol 1991; 61: 236–248 [DOI] [PubMed] [Google Scholar]
  • 46. Johnson RT, Griffin DE, Hirsch RL, et al. Measles encephalomyelitis: clinical and immunological studies. N Engl J Med 1984; 310: 137–141 [DOI] [PubMed] [Google Scholar]
  • 47. Lebon P, Boutin B, Dulac O, et al. Interferon‐τ in acute and subacute encephalitis. Br Med J 1988; 296: 9–11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Griffin DE, Ward BJ, Juaregui E, et al. Immune activation during measles: b̃2‐microglobulin in plasma and cerebrospinal fluid in complicated and uncomplicated disease. J Infect Dis 1992; 166: 1170–1173 [DOI] [PubMed] [Google Scholar]
  • 49. Moench TR, Griffin DE, Obriecht CR, et al. Distribution of measles virus antigen and RNA in acute measles with and with‐out neurologic involvement. J Infect Dis 1988; 158: 433–442 [DOI] [PubMed] [Google Scholar]
  • 50. Esolen LM, Ward BJ, Moench TR, et al. Infection of monocytes during measles. J Infect Dis 1993; 168: 47–52 [DOI] [PubMed] [Google Scholar]
  • 51. Centers for Disease Control . Pneumocystis pneumonia—Los Angeles. Morb Mortal Week Rep 1981; 30: 250–252 [PubMed] [Google Scholar]
  • 52. Centers for Disease Control . Kaposi's sarcoma and Pneumocystis pneumonia among homosexual men—New York City and California. Morb Mortal Week Rep 1981; 30: 305–308 [PubMed] [Google Scholar]
  • 53. Ho DD, Rota TR, Schooley RT, et al. Isolation of HTLV‐III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med 1985; 313: 1493–1497 [DOI] [PubMed] [Google Scholar]
  • 54. Levy JA, Shimabukuro J, Hollander H, et al. Isolation of AIDS‐associated retroviruses from cerebrospinal fluid and brain of patients with neurological symptoms. Lancet 1985; 2: 586–588 [PubMed] [Google Scholar]
  • 55. Shaw GM, Harper ME, Hahn BH, et al. HTLV‐III infection in brains of children and adults with AIDS encephalopathy. Science 1985; 227: 177–182 [DOI] [PubMed] [Google Scholar]
  • 56. Resnick L, DiMarzo‐Veronese F, Schüpbach J, et al. Intra‐blood‐brain‐barrier synthesis of HTLV‐III‐specific IgG in patients with neurologic symptoms associated with AIDS or AIDS‐related complex. N Engl J Med 1985; 313: 1498–1504 [DOI] [PubMed] [Google Scholar]
  • 57. Gonda MA, Wong‐Staal F, Gallo RC, et al. Sequence homology and morphologic similarity of HTLV‐III and visna virus, a pathogenic lentivirus. Science 1985; 227: 173–177 [DOI] [PubMed] [Google Scholar]
  • 58. McArthur JC. Neurologic manifestations of AIDS. Medicine 1987; 66: 407–437 [DOI] [PubMed] [Google Scholar]
  • 59. Johnson RT, McArthur JC, Narayan O. The neurobiology of human immunodeficiency virus infections. FASEB J 1988; 2: 2970–2981 [DOI] [PubMed] [Google Scholar]
  • 60. Navia BA, Cho E‐S, Petito CK, et al. The AIDS dementia complex: II. Neuropathology. Ann Neurol 1986; 19: 525–535 [DOI] [PubMed] [Google Scholar]
  • 61. Patito CK, Navia BA, Cho E‐S, et al. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 1985; 312: 874–879 [DOI] [PubMed] [Google Scholar]
  • 62. Schmidbauer M, Huemer M, Cristina S, et al. Morphological spectrum, distribution and clinical correlation of white matter lesions in AIDS brains. Neuropathol Appl Neurobiol 1882; 18: 489–501 [DOI] [PubMed] [Google Scholar]
  • 63. Power C, P‐A Kong,, Crawford TO, et al. Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood‐brain barrier. Ann Neurol 1993; 34: 339–350 [DOI] [PubMed] [Google Scholar]
  • 64. Becker PS, Griffin JW, McArthur JC, et al. Vacuolar myelopathy in human immunodeficiency virus (HIV) infection: central remyelination. J Neuropathol Exp Neurol 1989; 48: 383 (Abstract) [Google Scholar]
  • 65. Genis P, Jett M, Bernton EW, et al. Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)‐infected macrophage‐astroglia interactions: implications for the neuropathogenesis of HIV disease. J Exp Med 1992; 176: 1703–1718 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Lipton SA. HIV‐related neurotoxicity. Brain Pathol 1991; 1: 193–199 [DOI] [PubMed] [Google Scholar]
  • 67. Kennedy PGE, Narayan O, Ghotbi Z, et al. Persistent expression of Ia antigen and viral genome in visna‐maedi virus‐induced inflammatory cells: possible role of lentivirus‐induced interferon. J Exp Med 1985; 162: 1970–1982 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Wesselingh SL, Power C, Glass JD, et al. Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol 1993; 33: 576–582 [DOI] [PubMed] [Google Scholar]
  • 69. Tyor WR, Glass JD, Baumrind N, et al. Cytokine expression of macrophages in HIV‐1‐associated vacuolar myelopathy. Neurology 1993; 43: 1002–1009 [DOI] [PubMed] [Google Scholar]
  • 70. Margulis MS, Soloviev VD, Schubladze AK. Aetiology and pathogenesis of acute sporadic disseminated encephalomyelitis and multiple sclerosis. J Neurol Neurosurg Psychiatry 1946; 9: 62–74 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71. Bychkova EN. Viruses isolated from patients with encephalomyelitis and multiple sclerosis. I. Pathogenic and antigenic properties. Vopr Virusol 1964; 9: 173–176 [PubMed] [Google Scholar]
  • 72. Gudnadottir M, Helgadottir H, Bjarnason O, et al. Virus isolated from the brain of a patient with multiple sclerosis. Exp Neurol 1964; 9: 85–95 [DOI] [PubMed] [Google Scholar]
  • 73. Palsson PA, Pattison IH, Field EJ. Transmission experiments with multiple sclerosis In: Gajdusek CJ, Gibbs CJ, Jr, Alpers M, eds. Slow, latent and temperate virus infections. Washington, DC: US Government Printing Office, 1965: 49–54 [Google Scholar]
  • 74. Carp RI, Lucursi PC, Merz PA, et al. Decreased percentage of polymorphonuclear neutrophils in mouse peripheral blood after inoculation with material from multiple sclerosis patients. J Exp Med 1972; 136: 618–629 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75. Ter Meulen V, Koprowski H, Iwasaki Y, et al. Fusion of cultured multiple sclerosis brain cells with indicator cells—presence of nucleocapsids and virions and isolation of parainfluenza‐type virus. Lancet 1972; 2: 1–5 [DOI] [PubMed] [Google Scholar]
  • 76. Field EJ, Cowshall S, Narang HK, et al. Viruses in multiple sclerosis? Lancet 1972; 2: 280–281 [DOI] [PubMed] [Google Scholar]
  • 77. Mitchell DN, Porterfield JS, Micheletti R, et al. Isolation of an infectious agent from bone‐marrows of patients with multiple sclerosis. Lancet 1978; 2: 387–390 [DOI] [PubMed] [Google Scholar]
  • 78. Wrobleska Z, Gilden D, Devlin M, et al. Cytomegalovirus isolation from a chimpanzee with acute demyelinating disease after inoculation of multiple sclerosis brain cells. Infect Immun 1979; 25: 1008–1015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79. Burks JS, Devald BL, Jankovsky LD, et al. Two coronaviruses isolated from central nervous system tissue of two multiple sclerosis patients. Science 1980; 209: 933–934 [DOI] [PubMed] [Google Scholar]
  • 80. Melnick JL, Seidel E, Inoue YK, et al. Isolation of virus from the spinal fluid of three patients with multiple sclerosis and one with amyotrophic lateral sclerosis. Lancet 1982; 1: 830–833 [DOI] [PubMed] [Google Scholar]
  • 81. Vagabov RMA, Skortsoa TM, Gofman YP, et al. Isolation of the tick‐borne encephalitis virus from a patient with multiple sclerosis. Acta Virol 1982; 20: 403 [PubMed] [Google Scholar]
  • 82. Koprowski H, DeFreitas EC, Harper ME, et al. Multiple sclerosis and human T‐cell lymphotropic retroviruses. Nature 1985; 318: 154–160 [DOI] [PubMed] [Google Scholar]
  • 83. Perron H, Geny C, Laurent A, et al. Leptomeningeal cell line from multiple sclerosis with reverse transcriptase activity and viral particles. Res Virol 1989; 140: 551–561 [DOI] [PubMed] [Google Scholar]
  • 84. Bergström T, Andersen O, Vahlne A. Isolation of herpes simplex virus type 1 during first attack of multiple sclerosis. Ann Neurol 1989; 26: 283–285 [DOI] [PubMed] [Google Scholar]
  • 85. Johnson RT. Viral aspects of multiple sclerosis In: Vinken PJ, Bruyn GW, Klawans HL, eds. Handbook of clinical neurology. Amsterdam: Elsevier, 1985: 319–336 [Google Scholar]
  • 86. Johnson RT, Gibbs CJ Jr. Koch's postulates and slow infections of the nervous system. Arch Neurol 1974; 30: 36–38 [DOI] [PubMed] [Google Scholar]
  • 87. Dyson FJ. Unfashionable pursuits In Hanle H, ed. Alexander von Humboldt foundation, bi‐national colloquium for Humboldt awardees in cooperation with the Institute for Advanced Study, Princeton, New Jersey, August 23–26, 1981. Bonn: Bad Godesberg, 1982: 29–40 [Google Scholar]

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