Abstract
Viral induced demyelination, in both humans and rodent models, has provided unique insights into the cell biology of oligodendroglia, their complex cell‐cell interactions and mechanisms of myelin destruction. They illustrate mechanisms of viral persistence, including latent infections in which no infectious virus is readily evident, virus reactivation and viral‐induced tissue damage. These studies have also provided excellent paradigms to study the interactions between the immune system and the central nervous system (CNS). Although of interest in their own right, an understanding of the diverse mechanisms used by viruses to induce demyelination may shed light into the etiology and pathogenesis of the common demyelinating disorder multiple sclerosis (MS). This notion is supported by the persistent view that a viral infection acquired during adolescence might initiate MS after a long period of quiescence.
Demyelination in both humans and rodents can be initiated by infection with a diverse group of enveloped and non‐enveloped RNA and DNA viruses (Table 1). The mechanisms that ultimately result in the loss of CNS myelin appear to be equally diverse as the etiological agents capable of causing diseases which result in demyelination. Although demyelination can be a secondary result of axonal loss, in many examples of viral induced demyelination, myelin loss is primary and associated with axonal sparing. This suggests that demyelination induced by viral infections can result from: 1) a direct viral infection of oligodendroglia resulting in cell death with degeneration of myelin and its subsequent removal; 2) a persistent viral infection, in the presence or absence of infectious virus, resulting in the loss of normal cellular homeostasis and subsequent oligodendroglial death; 3) a vigorous virus‐specific inflammatory response wherein the virus replicates in a cell type other than oligodendroglia, but cytokines and other immune mediators directly damage the oligodendroglia or the myelin sheath; or 4) infection initiates activation of an immune response specific for either oligodendroglia or myelin components. Virus‐induced inflammation may be associated with the processing of myelin or oligodendroglial components and their presentation to the host's own T cell compartment. Alternatively, antigenic epitopes derived from the viral proteins may exhibit sufficient homology to host components that the immune response to the virus activates autoreactive T cells, i.e. molecular mimicry. Although it is not clear that each of these potential mechanisms participates in the pathogenesis of human demyelinating disease, analysis of the diverse demyelinating viral infections of both humans and rodents provides examples of many of these potential mechanisms.
Full Text
The Full Text of this article is available as a PDF (516.7 KB).
References
- 1. Adami C, Pooley J, Glomb J, Stecker E, Fazal F, Fleming JO, Baker SC (1995) Evolution of mouse hepatitis virus (MHV) during chronic infection: Quasispecies nature of the persisting MHV RNA. Virol 209:337–346. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Bailey OT, Pappenheimer AM, Cheever FS, Daniels JB (1949) A murine hepatitis virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin. II. Pathology. J Exp Med 90:195–212. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Barbano RL, Dal Canto MC (1984). Serum and cells from Theiler's virus‐infected mice fail to injure myelinating cultures or to produce in vivo transfer of diseases. The pathogenesis of Theiler's virus‐induced demyelination appears to differ from that of EAE. J Neurol Sci 66:283–293. [DOI] [PubMed] [Google Scholar]
- 4. Begolka WS, Vanderlugt CL, Rahbe SM, Miller SD (1998) Differential expression of inflammatory cytokines parallels progression of central nervous system pathology in two clinically distinct models of multiple sclerosis. J Immunol 161:4437–4446. [PubMed] [Google Scholar]
- 5. Barac‐Latas V, Suchanek G, Breitschopf H, Stuehler A, Wege H, Lassmann H (1997) Patterns of oligodendrocyte pathology in coronavirus‐induced subacute demyelinating encephalomyelitis in the Lewis rat. Glia 19:1–12. [DOI] [PubMed] [Google Scholar]
- 6. Bergmann, C , Altman, J , Hinton, DR , Stohlman SA (1999) Inverted immunodominance and impaired cytolytic function of CD8+ T cells during viral persistence in the CNS. J Immunol 163:3379–3387. [PubMed] [Google Scholar]
- 7. Bjartmar C, Yin X, Trapp BD (1999) Axonal pathology in myelin disorders. J Neurocytol 28:383–395. [DOI] [PubMed] [Google Scholar]
- 8. Bonetti B, Pohl J, Gao YL, Raine CS (1997) Cell death during autoimmune demyelination: effector but not target cells are eliminated by apoptosis. J Immunol 159:5733–41. [PubMed] [Google Scholar]
- 9. Borrow P, Tonks P, Welsh CJ, Nash AA (1992) The role of CD8+ T cells in the acute and chronic phases of Theiler's murine encephalomyelitis virus‐induced disease in mice. J Gen Virol 73:1861–1865. [DOI] [PubMed] [Google Scholar]
- 10. Bouteille M, Fontaine C, Vedrenne CL, Delarue J (1965) Sur un cas d'encephalite subaigue a inclusions. Etude anatomoclinique et ultrastructurale. Rev Neurol 113:454–458. [Google Scholar]
- 11. Castro RF, Perlman S (1996) CD8+ T‐cell epitopes within the surface glycoprotein of a neurotropic coronavirus and correlation with pathogenicity. J Virol 69:8127–8131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Cattaneo R, Schmid A, Billeter MA et al. (1988) Multiple viral mutations rather than host factors cause defective measles virus gene expression in a subacute sclerosing panencephalitis cell line. J Virol 62:1388–1397. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Cheever FS, Daniels JB, Pappenheimer AM, Bailey OT (1949) A murine virus (JHM) causing disseminated encephalomyelitis with extensive destruction of myelin. J Exp Med 90:181–194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Chesters PM, Heritage J, McCance D (1983) Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis 147:676–682. [DOI] [PubMed] [Google Scholar]
- 15. Clatch RJ, Lipton HL, Miller SD (1986). Characterization of Theiler's murine encephalomyelitis virus (TMEV)‐specific delayed‐type hypersensitivity responses in TMEV‐induced demyelinating disease: correlation with clinical signs. J Immunol 136:920–927. [PubMed] [Google Scholar]
- 16. Coleman DV, Gardner SD, Field AM (1973) Human papovavirus infection in renal allograft recipients. Br Med J 3:371–375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Connolly JH, Allen IV, Hurwitz LJ, Millar JH (1967) Measles‐virus antibody and antigen in subacute sclerosing panencephalitis. Lancet 1:542–544. [DOI] [PubMed] [Google Scholar]
- 18. Das Sarma J, Fu L, Tsai JC, Weiss SR, Lavi E (2000) Demyelination determinants map to the spike glycoprotein gene of coronavirus mouse hepatitis virus. J Virol 74:9206–9213. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Dawson J (1933) Cellular inclusions in cerebral lesions of lethargic encephalitis. Am J Pathol 9, 7–16. [PMC free article] [PubMed] [Google Scholar]
- 20. Del Canto MC, Lipton HL (1975) Primary demyelination in Theiler's virus infection. An ultrastructural study. Lab Invest 33:626–637. [PubMed] [Google Scholar]
- 21. Dethlefs S, Brahic M, Larsson‐Sciard P (1997) An early, abundant cytotoxic T lymphocyte response against Theiler's virus is critical for preventing viral persistence J Virol 71:8875–8878. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Dhib‐Jalbut S, McFarland HF, Mingioli ES, Sever JL, McFarlin DE (1988) Humoral and cellular immune responses to matrix protein of measles virus in subacute sclerosing panencephalitis. J Virol 62:2483–2489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Dix RD, Palm SE (1993) Opportunistic infections of the central nervous system during AIDS. Adv Neuroimmunol 3:81–96. [Google Scholar]
- 24. Erlich S, Fleming J, Stohlman S, Weiner L (1987) Experimental neuropathology of remote infection with a JHM virus variant (DS). Arch Neurol 44:839–842. [DOI] [PubMed] [Google Scholar]
- 25. Fiette L, Aubert C, Brahic M, Rossi CP (1993) Theiler's virus infection of beta 2‐microglobulin‐deficient mice. J Virol 67:589–592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Fleming JO, Trousdale M, El‐Zaatari F, Stohlman SA, Weiner LP (1986) Pathogenicity of antigenic variants of murine coronavirus JHM selected with monoclonal antibodies. J Virol 58:869–875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Fleming JO, Wang F‐I, Trousdale MT, Hinton DR, Stohlman SA (1993) Interaction of immune and central nervous systems: Contribution of anti‐viral Thy‐1+ cells to demyelination induced by coronavirus JHM. Regional Immunol 5:37–43. [PubMed] [Google Scholar]
- 28. Fujinami RS, Oldstone MBA (1980) Alterations in expression of measles virus polypeptides by antibody: molecular events in antibody‐induced antigenic modulation. J Immunol 125:78–85. [PubMed] [Google Scholar]
- 29. Fujinami RS, Oldstone MB (1985) Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science 230:1043–1045. [DOI] [PubMed] [Google Scholar]
- 30. Gallagher TM, Parker SE, Buchmeier MJ (1990) Neutralization‐resistant variants of a neurotropic coronavirus are generated by deletions within the amino‐terminal half of the spike glycoprotein. J Virol 64:731–741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Gerety, SJ , Rundell, MK , Dal Canto MC, Miller SD (1994) Class II‐restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)‐induced demyelinating disease. VI. Potentiation of demyelination with and characterization of an immunopathologic CD4+ T cell line specific for an immunodominant VP2 epitope. J Immunol 152:919–929. [PubMed] [Google Scholar]
- 32. Gimsa U, Peter SV, Lehmann K, Bechmann I, Nitsch R (2000) Axonal damage induced by invading T cells in organotypic central nervous system tissue in vitro: involvement of microglial cells. Brain Pathol 10:365–377. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Gombold J, Sutherland R, Lavi E, Paterson Y, Weiss SR (1995). Mouse hepatitis virus A59‐induced demyelination can occur in the absence of CD8+ T cells. Microb Pathog 18:211–221. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Griffin DE, Levine B, Tylor W, Ubol S, Despres P (1997) The role of antibody in recovery from alphavirus encephalitis. Immunol Rev 159:155–161. [DOI] [PubMed] [Google Scholar]
- 35. Hall WW, Lamb RA, Choppin PW (1979) Measles and SSPE virus proteins: Lack of antibodies to the M protein in patients with subacute sclerosing paenencephalitis. Proc Natl Acad Sci USA 76:2047–2051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Hall WW, Choppin PW (1979) Evidence for lack of synthesis of the M polypeptide of measles virus in brain cells in subacute panencephalitis. Virology 99:443–447. [DOI] [PubMed] [Google Scholar]
- 37. Hall WW, Choppin PW (1981) Measles virus proteins in the brain tissue of patients with subacute sclerosing panencephalitis. N Engl J Med 304:1152–1155. [DOI] [PubMed] [Google Scholar]
- 38. Hanninen P, Arstila P, Lang H, Salmi A, Panelius M (1980) Involvement of the central nervous system in acute, uncomplicated measles virus infection. J Clin Microbiol 11:610–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Haspel MV, Lampert PW, Oldstone MBA (1978) Temperature‐sensitive mutants of mouse hepatitis virus produce a high incidence of demyelination. PNAS 75:4033–4036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Hensen J, Rosenblum M, Armstrong D, Furneaux H (1991) Amplification of JC virus DNA from brain and cerebrospinal fluid of patients with progressive multifocal leucoencephalopathy. Neurol 41:1967–1971. [DOI] [PubMed] [Google Scholar]
- 41. Herndon RM, Rubinstein LJ (1967) Light and electron microscopy observations in the development of viral particles in the inclusions of Dawson's encephalitis (subacute sclerosing panencephalitis) Neurol 18:8–20. [DOI] [PubMed] [Google Scholar]
- 42. Herndon RM, Griffin DE, McCormick U, Weiner LP (1975) Mouse hepatitis virus‐induced recurrent demyelination. Arch Neurol 32:32–35. [DOI] [PubMed] [Google Scholar]
- 43. Herndon RM, Price DL, Weiner LP (1977) Regeneration of oligodendroglia during recovery from demyelinating disease. Science 195:693–694. [DOI] [PubMed] [Google Scholar]
- 44. Hickey W F, Hsu B L, Kimura H (1991) T lymphocyte entry into the central nervous system. J Neurosci Res 28:254. [DOI] [PubMed] [Google Scholar]
- 45. Hofman FM, Hinton DR, Baemayr J, Weil M, Merrill JE (1991) Lymphokines and immunoregulatory molecules in subacute sclerosing panencephalitis. Clin Immunopathol 58:331–342. [DOI] [PubMed] [Google Scholar]
- 46. Horta‐Barbosa L, Fuccilo DA, Sever JL, Zeman W (1969) Subacute sclerosing panencephalitis: isolation of a measles virus from a brain biopsy. Nature 221:974. [DOI] [PubMed] [Google Scholar]
- 47. Hou J, Major EO (2000) Progressive multifocal leukoencephalopathy: JC virus induced demyelination in the immune compromised host. J Neurovirol 6:98–100. [PubMed] [Google Scholar]
- 48. Ikeda K, Abiyama H, Kondo H, Arai T, Arai N, Yagashita S (1995) Numerous glial fibrillary tangles in oligodendroglia in cases of subacute sclerosing panencephalitis with neurofibrillary tangles. Neurosci Lett 194: 133–135. [DOI] [PubMed] [Google Scholar]
- 49. Jenis EH, Knieser MR, Rothouse PA, Jensen GE, Scott RM. (1973) Subacute sclerosing panencephalitis. Immunoultrastructural localization of measles‐virus antigen. Arch Pathol Lab Med 95:81–9. [PubMed] [Google Scholar]
- 50. Kim BS, Palma JP (1999) Immune mechanisms of Theiler's virus induced demyelination Exp Mol Med 3:115–121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Knobler RL, Lampert PW, Oldstone MBA (1982) Virus persistence and recurring demyelination produced by a temperature‐sensitive mutant of MHV‐4. Nature 298:279–280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Knopf, PM , Harling‐Berg CJ, Cserr, HF , Basu D, Sirulnick EJ, Nolan SC, Park JT, Keir G, Thompson EJ, Hickey WF (1998) Antigen‐dependent intrathecal synthesis in the normal rat brain: Tissue entry and local retention of antigen‐specific B cells. J Immunol 161: 692–701. [PubMed] [Google Scholar]
- 53. Kurtzke JF (1993) Epidemiologic evidence for multiple sclerosis as an infection. Clin Microbiol Rev 6:382–427. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54. Kyuwa S, Yamaguchi K, Toyoda Y, Fujiwara K (1991) Induction of self‐reactive T cells after murine infection. J Virol 65:1789–1795. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Lampert PW, Sims JK, Kniazeff AJ (1973) Mechanism of demyelination in JHM virus encephalomyelitis. Acta Neuropathol 24:76–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56. Lavi E, Gilden DH, Wroblewska Z, Rorke LB, Weiss SR (1984) Experimental demyelination produced by the A59 strain of mouse hepatitis virus. Neurol 34:597–603. [DOI] [PubMed] [Google Scholar]
- 57. Liebert UG, Schneider‐Schaulies S, Baczko K, Ter Meulen V (1990) Antibody‐induced restriction of viral gene expression in measles encephalitis in rats. J Virol 64:706–713. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58. Lin MT, Hinton DR, Stohlman SA (1997) Mouse hepatitis virus is cleared from the central nervous system of mice lacking perforin‐mediated cytolysis. J Virol 71:383–391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59. Lin, MT , Hinton, DR , Parra B, Stohlman SA, van der Veen RC (1998) The role of IL‐10 in mouse hepatitis virus‐induced encephalomyelitis. Virology 245:270–280. [DOI] [PubMed] [Google Scholar]
- 60. Lin, MT , Hinton, DR , Marten, NW , Bergmann, CC , Stohlman SA (1999) Antibody prevents virus reactivation within the central nervous system. J Immunol 162:7358–7368. [PubMed] [Google Scholar]
- 61. Lipton HL (1975) Theiler's virus infection in mice: An unusual biphasic disease process leading to demyelination. Infect Immun 11:1147–1155. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Marten N, Stohlman S, Bergmann CC (2000) Role of Viral Persistence in Retaining CD8+ T cells within the central nervous system. J Virol 74:7903–7910. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. McGraven BD, Murray PD, Rodriguez M (1999) Quantitation of spinal cord demyelination, remyelination, atrophy, and axonal loss in a model of progressive neurological injury. J Neurosci Res 58:492–504. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. McGavern BD, Murray PD, Rivera‐Quinones C, Schmelzer JD, Low PA, Rodriguez M (2000) Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis. Brain 123:519–531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65. Mehal WZ, Esiri MM, Lo Y‐MD et al (1993) Detection of reactivation and size variation in the regulatory region of JC virus in brain tissue. J Clin Pathol 46:646–649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Miller SD, Clatch RJ, Pevear DC, Trotter JL, Lipton HL (1987) Class II‐restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)‐induced demyelinating disease. I. Cross‐specificity among TMEV sub‐strains and related picoronaviruses, but not myelin proteins. J Immunol 138:3776–3784. [PubMed] [Google Scholar]
- 67. Miller SD, Gerety SJ, Kennedy MK, Peterson JD, Trotter JL, Tuohy VK, Waltenbaugh C, Dal Canto MC, Lipton HL (1990) Class II‐restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)‐induced demyelinating disease. III. Failure of neuroantigen‐specific immune tolerance to affect the clinical course of demyelination. J Neuroimmunol 26:9–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Miller SD, Vanderlugt CL, Begolka WS, Pao W, Yauch RL, Neville KL, Katz‐Levy Y, Carrizosa A, Kim BS (1997) Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading. Nature Med 3:1133–1136. [DOI] [PubMed] [Google Scholar]
- 69. Modlin JF, Jabbour JR, Witte JJ, Halsey NA. (1977) Epidemiologic studies of measles; measles vaccines and subacute sclerosing panencephalitis. Pediatrics 59:505–512. [PubMed] [Google Scholar]
- 70. Modlin JF, Halsey NA, Eddins DL, Conrad JL, Jabbour JT, Chien L, Robinson H (1979) Epidemiology of subacute sclerosing panencephalitis. J Pediatrics 94:231–236. [DOI] [PubMed] [Google Scholar]
- 71. Murray PD, McGraven DB, Lin X, Njenja MK, Leibowitz J, Pease LR, Rodriguez M (1998) Perforin‐dependent neurological injury in a viral model of multiple sclerosis. J Neurosci 18:7305–7314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72. Murray RS, Cai G‐Y, Hoel K, Zhang J‐Y, Soike KF, Cabirac GF (1992) Coronavirus infects and causes demyelination in primate central nervous system. Virol 199:274–284. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73. Nagano I, Nakamura S, Yoshioka M, Onodera J, Kogure K, Itoyama Y (1994) Expression of cytokines in brain lesions in subacute sclerosing panencephalitis. Neurology 44:710–715. [DOI] [PubMed] [Google Scholar]
- 74. Oldstone MBA, Boskisch VA, Dixon, FJ (1975) Subacute sclerosing panencephalitis: Destruction of human brain cells by antibody and complement in an autologous system. Clin Immunol Immunopath 4:52–58. [DOI] [PubMed] [Google Scholar]
- 75. Padgett BL, Walker DL, ZuRhein GM et al (1971) Cultivation of a papovavirus‐like virus from human brain with progressive multifocal leukoencephalopathy. Lancet 1: 1257–1260. [DOI] [PubMed] [Google Scholar]
- 76. Padgett BL, Walker DL (1973) Prevalence of antibodies in human sera against JC virus: an isolate from a case of progressive multifocal leukoencephalopathy. J Inf Dis 127:467–470. [DOI] [PubMed] [Google Scholar]
- 77. Parker JC, Klintworth GK, Graham DG, Griffith JF (1970) Uncommon morphologic features in subacute sclerosing panencephalitis (SSPE). Am J Pathol 2:275–292. [PMC free article] [PubMed] [Google Scholar]
- 78. Parra B, Hinton DR, Marten N, Bergmann CC, Lin, M , Yang C, Stohlman SA (1999) Gamma interferon is required for viral clearance from central nervous system oligodendroglia. J Immunol 162: 1641–1647. [PubMed] [Google Scholar]
- 79. Parra B, Lin M, Stohlman S, Bergmann CC, Atkinson R, Hinton DR (2000) Contributions of Fas‐Fas ligand interactions to the pathogenesis of mouse hepatitis virus in the central nervous system. J Virol 74:2447–2450. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80. Payne FE, Baublis JV, Habashi HH (1969) Isolation of measles virus from cell cultures of brain from a patient with subacute sclerosing panencephalitis. New Engl J Med 281:585–589. [DOI] [PubMed] [Google Scholar]
- 81. Pearce BD, Hobbs MV, McGraw TS, Buchmeier MJ (1994) Cytokine induction during T‐cell‐mediated clearance of mouse hepatitis virus from neurons in vivo . J Virol 8:5483–5495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82. Perlman S, Schelper R, Bolger E, Ries D (1987) Late onset, symptomatic, demyelinating encephalomyelitis in mice infected with MHV‐JHM in the presence of maternal antibody. Microb Pathogen 2:185–194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 83. Perier O. Vanderhaeghen J.J. Pelc S. Subacute sclerosing leuco‐encephalitis. (1967) Electron microscopic finding in two cases with inclusion bodies. Acta Neuropathol 8:362–80. [DOI] [PubMed] [Google Scholar]
- 84. Phillips JJ. Chua MM. Lavi E. Weiss SR (1999) Pathogenesis of chimeric MHV4/MHV‐A59 recombinant viruses: the murine coronavirus spike protein is a major determinant of neurovirulence. J Virol 73:7752–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85. Pope JG, Karpus WJ, Vanderlugt CL, Miller SD (1996) Flow cytometric and functional analyses of CNS‐infiltrating cells in SJL/J mice with Theiler's virus‐induced demyelinating disease: Evidence for a CD4+ T cell‐mediated pathology. J Immunol 156:4050–4058. [PubMed] [Google Scholar]
- 86. Powell HC, Lampert PW (1975) Oligodendrocytes and their myelin‐plasma membrane connections in JHM mouse hepatitis virus encephalomyelitis. Lab Invest 33:440–445. [PubMed] [Google Scholar]
- 87. Power C, Gladden JG, Halliday W, Del Bigio MR, Nath A, Ni W, Major EO, Blanchard J, Mowat M (2000) AIDS‐and non‐AIDS‐related PML association with distinct p53 polymorphism. Neurology 54:743–746. [DOI] [PubMed] [Google Scholar]
- 88. Rammohan KW, McFarland HF, Bellini WJ, Gheuens J, McFarlin DE (1981) Antibody‐mediated modification of encephalitis induced by hamster neurotropic measles virus. J Infect Dis 147:546–549. [DOI] [PubMed] [Google Scholar]
- 89. Rammohan KW, McFarland HF, McFarlin DE. (1981) Induction of subacute murine measles encephalitis by monoclonal antibody to virus haemagglutinin. Nature 290:588–589. [DOI] [PubMed] [Google Scholar]
- 90. Rivera‐Quinones C, McGavern D, Schmelzer JD, Hunter SF, Low PA, Rodrigues M (1998) Absence of neurological deficits following extensive demyelination in a class I‐deficient murine model of multiple sclerosis. Nat Med 4:187–193. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 91. Ruddle NH, Bergman CK, McGrath KM, Lingenheld EG, Grunnet ML, Padula SJ, Clark RB (1990) An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J Exp Med 172:1193–1200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92. Sa MJ, Madeira D, Cruz C, Paula‐Barbosa MM (1995) Morphometric study of the frontal cortex in subacute sclerosing panencephalitis. Acta Neurol Scand 92:225–230. [DOI] [PubMed] [Google Scholar]
- 93. Samorei IW, Schmid M, Pawlita M, Vinters HV, Diebold K, Mundt C, von Einsiedel RW (2000). High sensitivity detection of JC‐virus DNA in postmortem brain tissue by in situ PCR. J Neurovirol 6:61–74. [DOI] [PubMed] [Google Scholar]
- 94. Selmaj KW, Raine CS (1988) Tumor necrosis factor mediated myelin and oligodendroglia damage in vitro . Ann Neurol 23:339–346. [DOI] [PubMed] [Google Scholar]
- 95. Stohlman SA, Weiner LP (1981) Chronic nervous system demyelination in mice after JHM virus infection. Neurology 31:38–44. [DOI] [PubMed] [Google Scholar]
- 96. Stohlman SA, Matsushima GK, Casteel N, Weiner LP (1986) In vivo effects of coronavirus‐specific T cell clones: DTH Inducer cells prevent a lethal infection but do not inhibit virus replication. J Immunol 1986; 136:3052–3056. [PubMed] [Google Scholar]
- 97. Stohlman SA, Kyuwa S, Polo J, Brady D, Lai MMC, Bergmann C (1993) Characterization of mouse hepatitis virus specific cytotoxic T cells derived from the central nervous system of mice infected with the JHM strain. J Virol 67:7050–7059. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98. Stohlman SA, Hinton DR, Cua D, Dimacali E, Sensintaffar J, Tahara S, Hofman F, Yao Q (1995) Tumor necrosis factor expression during mouse hepatitis virus induced demyelination. J Virol 69:5898–5903. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 99. Stohlman SA, Bergmann C, van der Veen R, Hinton D (1995) Mouse hepatitis virus ‐specific cytotoxic T lymphocytes protect from lethal infection without eliminating virus from oligodendroglia. J Virol 69:684–694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100. Stohlman SA, Bergmann CC, Lin MT, Cua DJ, Hinton DR (1998) CTL effector function within the CNS requires CD4+ T cells. J Immunol 160: 2896–2904. [PubMed] [Google Scholar]
- 101. Stohlman, S , Bergmann, C , Perlman S (1999) Persistent Infection by Mouse Hepatitis Virus In: Persistent Viral Infections, ed. Ahmed R. and Chen I.. p. 537–558 John Wiley; New York . [Google Scholar]
- 102. Sun N, Grzybicki D, Castro R, Muphy S, Perlman S (1995) Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus. Virology 213:482–493. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 103. Tornatore C, Berger JR, Houff, SA et al. (1992) Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy. Ann Neurol 31:454–462. [DOI] [PubMed] [Google Scholar]
- 104. Tellez‐Nagel I, Harter DH (1966) Subacute sclerosing leukoencephalitis: ultrastructure of intranuclear and intracytoplasmic inclusions. Science 154:899–901. [DOI] [PubMed] [Google Scholar]
- 105. Theiler, M (1937) Spontaneous encephalomyelitis of mice, a new virus disease. J Exp Med 65:705–719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 106. Theiler M, Gard S (1940) Encephalomyelitis of mice. J Exp Med 72:49–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107. Ure D, Rodrigues M (2000) Extensive injury of descending neurons demonstrated by retrograde labeling in a virus‐induced model of chronic inflammatory demyelination. J Neuropathol Exp Neurol 59:664–678. [DOI] [PubMed] [Google Scholar]
- 108. Valle LD, Croul S, Morgello S, Amini S, Rappaport J, Khalili K (2000) Detection of HIV‐1 Tat and JC nucleocapsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy. J Neurovirol 6:221–228. [DOI] [PubMed] [Google Scholar]
- 109. Wang F‐I, Hinton DR, Gilmore W, Trousdale MD, Fleming JO (1992) Sequential infection of glial cells by the murine hepatitis virus JHM strain (MHV‐4) leads to a characteristic distribution of demyelination. Lab Invest 66:744–754. [PubMed] [Google Scholar]
- 110. Watanabe R, Wege H, Ter Meulen V (1987) Comparative analysis of coronavirus JHM‐induced demyelinating encephalomyelitis in Lewis and Brown Norway rats. Lab Invest 57:375–383. [PubMed] [Google Scholar]
- 111. Wear DJ, Rapp F (1971) Latent measles virus infection of the hamster central nervous system. J Immunol 107:1593–1598. [PubMed] [Google Scholar]
- 112. Wege H, Watanabe R, Ter Meulen V (1984) Relapsing subacute demyelinating encephalomyelitis in rats during the course of coronavirus JHM infection. J Neuroimmunol 6:325–336. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 113. Weiner LP, Herndon RM, Narayan O et al. (1972) Isolation of a virus related to SV40 from patients with progressive multifocal leukoencephalopathy. New Engl J Med 286:385–390. [DOI] [PubMed] [Google Scholar]
- 114. Weiner LP (1973) Pathogenesis of demyelination induced by a mouse hepatitis virus (JHM virus). Acta Neurol 28:298–303. [DOI] [PubMed] [Google Scholar]
- 115. Williams RK, Jiang GS, Snyder SV, Frana MF, Holmes KV (1990) Purification of the 110‐kilodalton glycoprotein receptor for mouse hepatitis virus (MHV)‐A59 and identification of a non‐functional, homologous protein MHV‐resistant SJL/J mice. J Virol 64:3817–3823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116. Williamson JSP, Stohlman SA (1990) Effective clearance of mouse hepatitis virus from the CNS requires both CD4+ and CD8+ T cells. J Virol 64:4590–4592. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117. Williamson J, Sykes SPK, Stohlman S (1991) Characterization of brain infiltrating mononuclear cells during infection with mouse hepatitis virus strain JHM. J Neuroimmunol 32:199–207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118. Wisniewski HM, Bloom BR (1975) Primary demyelination as a non‐specific consequence of a cell‐mediated immune reaction. J Exp Med 141:346–359. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119. Woyciechowska JL, Trapp BD, Patrick DH, Shekarchi IC, Leinikki PO, Sever JL, Holmes KV. (1984) Acute and subacute demyelination induced by mouse hepatitis virus strain A59 in C3H mice. J Exp Path 1:295–306. [PubMed] [Google Scholar]
- 120. Wu GF, Perlman S (1999) Macrophage infiltration, but not apoptosis, is correlated with immune‐mediated demyelination following murine infection with a neurotropic coronavirus. J Virol 73:8771–8780. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121. Xue S, Sun N, Van Rooijen N, Perlman S (1999) Depletion of blood‐borne macrophages does not reduce demyelination in mice infected with a neurotropic coronavirus. J Virol 73:6327–6334. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. Zeman W, Kolar O (1968) Reflections on the etiology and pathogenesis of subacute sclerosing panencephalitis. Neurology 18:1–7. [DOI] [PubMed] [Google Scholar]
- 123. ZuRhein GM, Chou SM (1965) Particles resembling papovaviruses in human cerebral demyelinating disease. Science 148:1477–1479. [DOI] [PubMed] [Google Scholar]