Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1997 Jul;71(7):5287–5294. doi: 10.1128/jvi.71.7.5287-5294.1997

Neurologic disease induced by polytropic murine retroviruses: neurovirulence determined by efficiency of spread to microglial cells.

S J Robertson 1, K J Hasenkrug 1, B Chesebro 1, J L Portis 1
PMCID: PMC191765  PMID: 9188597

Abstract

Several murine leukemia viruses (MuLV) induce neurologic disease in susceptible mice. To identify features of central nervous system (CNS) infection that correlate with neurovirulence, we compared two neurovirulent MuLV, Fr98 and Fr98/SE, with a nonneurovirulent MuLV, Fr54. All three viruses utilize the polytropic receptor and are coisogenic, each containing a different envelope gene within a common genetic background. Both Fr98 and Fr98/SE induce a clinical neurologic disease characterized by hyperexcitability and ataxia yet differ in incubation period, 16 to 30 and 30 to 60 days, respectively. Fr54 infects the CNS but fails to induce clinical signs of neurologic disease. In this study, we compared the histopathology, regional virus distribution, and cell tropism in the brain, as well as the relative CNS viral burdens. All three viruses induced similar histopathologic effects, characterized by intense reactive astrogliosis and microglial activation associated with minimal vacuolar degeneration. The infected target cells for each virus consisted primarily of endothelial and microglial cells, with rare oligodendrocytes. Infection localized predominantly in white matter tracts of the cerebellum, internal capsule, and corpus callosum. The only feature that correlated with relative neurovirulence was viral burden as measured by both viral CA protein expression in cerebellar homogenates and quantification of infected cells. Interestingly, Fr54 (nonneurovirulent) and Fr98/SE (slow disease) had similar viral burdens at 3 weeks postinoculation, suggesting that they entered the brain with comparable efficiencies. However, spread of Fr98/SE within the brain thereafter exceeded that of Fr54, reaching levels of viral burden comparable to that seen for Fr98 (rapid disease) at 3 weeks. These results suggest that the determinants of neurovirulence in the envelope gene may influence the efficiency of virus spread within the brain and that a critical number of infected cells may be required for induction of clinical neurologic disease.

Full Text

The Full Text of this article is available as a PDF (711.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Achim C. L., Wang R., Miners D. K., Wiley C. A. Brain viral burden in HIV infection. J Neuropathol Exp Neurol. 1994 May;53(3):284–294. doi: 10.1097/00005072-199405000-00010. [DOI] [PubMed] [Google Scholar]
  2. Adamson D. C., Wildemann B., Sasaki M., Glass J. D., McArthur J. C., Christov V. I., Dawson T. M., Dawson V. L. Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science. 1996 Dec 13;274(5294):1917–1921. doi: 10.1126/science.274.5294.1917. [DOI] [PubMed] [Google Scholar]
  3. Baszler T. V., Zachary J. F. Murine retroviral neurovirulence correlates with an enhanced ability ofvirus to infect selectively, replicate in, and activate resident microglial cells. Am J Pathol. 1991 Mar;138(3):655–671. [PMC free article] [PubMed] [Google Scholar]
  4. Baszler T. V., Zachary J. F. Murine retroviral-induced spongiform neuronal degeneration parallels resident microglial cell infection: ultrastructural findings. Lab Invest. 1990 Nov;63(5):612–623. [PubMed] [Google Scholar]
  5. Bilello J. A., Pitts O. M., Hoffman P. M. Characterization of a progressive neurodegenerative disease induced by a temperature-sensitive Moloney murine leukemia virus infection. J Virol. 1986 Aug;59(2):234–241. doi: 10.1128/jvi.59.2.234-241.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Buller R. S., Wehrly K., Portis J. L., Chesebro B. Host genes conferring resistance to a central nervous system disease induced by a polytropic recombinant Friend murine retrovirus. J Virol. 1990 Feb;64(2):493–498. doi: 10.1128/jvi.64.2.493-498.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chesebro B., Wehrly K. Different murine cell lines manifest unique patterns of interference to superinfection by murine leukemia viruses. Virology. 1985 Feb;141(1):119–129. doi: 10.1016/0042-6822(85)90188-6. [DOI] [PubMed] [Google Scholar]
  8. Cork L. C., Hadlow W. J., Crawford T. B., Gorham J. R., Piper R. C. Infectious leukoencephalomyelitis of young goats. J Infect Dis. 1974 Feb;129(2):134–141. doi: 10.1093/infdis/129.2.134. [DOI] [PubMed] [Google Scholar]
  9. Czub M., Czub S., McAtee F. J., Portis J. L. Age-dependent resistance to murine retrovirus-induced spongiform neurodegeneration results from central nervous system-specific restriction of virus replication. J Virol. 1991 May;65(5):2539–2544. doi: 10.1128/jvi.65.5.2539-2544.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Czub M., McAtee F. J., Portis J. L. Murine retrovirus-induced spongiform encephalomyelopathy: host and viral factors which determine the length of the incubation period. J Virol. 1992 Jun;66(6):3298–3305. doi: 10.1128/jvi.66.6.3298-3305.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Czub S., Lynch W. P., Czub M., Portis J. L. Kinetic analysis of spongiform neurodegenerative disease induced by a highly virulent murine retrovirus. Lab Invest. 1994 May;70(5):711–723. [PubMed] [Google Scholar]
  12. DesGroseillers L., Barrette M., Jolicoeur P. Physical mapping of the paralysis-inducing determinant of a wild mouse ecotropic neurotropic retrovirus. J Virol. 1984 Nov;52(2):356–363. doi: 10.1128/jvi.52.2.356-363.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Dickson D. W., Lee S. C., Mattiace L. A., Yen S. H., Brosnan C. Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease. Glia. 1993 Jan;7(1):75–83. doi: 10.1002/glia.440070113. [DOI] [PubMed] [Google Scholar]
  14. Gardner M. B., Henderson B. E., Officer J. E., Rongey R. W., Parker J. C., Oliver C., Estes J. D., Huebner R. J. A spontaneous lower motor neuron disease apparently caused by indigenous type-C RNA virus in wild mice. J Natl Cancer Inst. 1973 Oct;51(4):1243–1254. doi: 10.1093/jnci/51.4.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Genis P., Jett M., Bernton E. W., Boyle T., Gelbard H. A., Dzenko K., Keane R. W., Resnick L., Mizrachi Y., Volsky D. J. 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 Dec 1;176(6):1703–1718. doi: 10.1084/jem.176.6.1703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Giulian D., Vaca K., Noonan C. A. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science. 1990 Dec 14;250(4987):1593–1596. doi: 10.1126/science.2148832. [DOI] [PubMed] [Google Scholar]
  17. Glass J. D., Fedor H., Wesselingh S. L., McArthur J. C. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol. 1995 Nov;38(5):755–762. doi: 10.1002/ana.410380510. [DOI] [PubMed] [Google Scholar]
  18. Hajihosseini M., Iavachev L., Price J. Evidence that retroviruses integrate into post-replication host DNA. EMBO J. 1993 Dec 15;12(13):4969–4974. doi: 10.1002/j.1460-2075.1993.tb06190.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hasenkrug K. J., Robertson S. J., Porti J., McAtee F., Nishio J., Chesebro B. Two separate envelope regions influence induction of brain disease by a polytropic murine retrovirus (FMCF98). J Virol. 1996 Jul;70(7):4825–4828. doi: 10.1128/jvi.70.7.4825-4828.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hoffman P. M., Cimino E. F., Robbins D. S., Broadwell R. D., Powers J. M., Ruscetti S. K. Cellular tropism and localization in the rodent nervous system of a neuropathogenic variant of Friend murine leukemia virus. Lab Invest. 1992 Sep;67(3):314–321. [PubMed] [Google Scholar]
  21. Johnson R. T., Glass J. D., McArthur J. C., Chesebro B. W. Quantitation of human immunodeficiency virus in brains of demented and nondemented patients with acquired immunodeficiency syndrome. Ann Neurol. 1996 Mar;39(3):392–395. doi: 10.1002/ana.410390319. [DOI] [PubMed] [Google Scholar]
  22. Johnson R. T., McArthur J. C., Narayan O. The neurobiology of human immunodeficiency virus infections. FASEB J. 1988 Nov;2(14):2970–2981. doi: 10.1096/fasebj.2.14.2846395. [DOI] [PubMed] [Google Scholar]
  23. Kai K., Furuta T. Isolation of paralysis-inducing murine leukemia viruses from Friend virus passaged in rats. J Virol. 1984 Jun;50(3):970–973. doi: 10.1128/jvi.50.3.970-973.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koenig S., Gendelman H. E., Orenstein J. M., Dal Canto M. C., Pezeshkpour G. H., Yungbluth M., Janotta F., Aksamit A., Martin M. A., Fauci A. S. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. doi: 10.1126/science.3016903. [DOI] [PubMed] [Google Scholar]
  25. Lynch W. P., Czub S., McAtee F. J., Hayes S. F., Portis J. L. Murine retrovirus-induced spongiform encephalopathy: productive infection of microglia and cerebellar neurons in accelerated CNS disease. Neuron. 1991 Sep;7(3):365–379. doi: 10.1016/0896-6273(91)90289-c. [DOI] [PubMed] [Google Scholar]
  26. Lynch W. P., Portis J. L. Murine retrovirus-induced spongiform encephalopathy: disease expression is dependent on postnatal development of the central nervous system. J Virol. 1993 May;67(5):2601–2610. doi: 10.1128/jvi.67.5.2601-2610.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lynch W. P., Robertson S. J., Portis J. L. Induction of focal spongiform neurodegeneration in developmentally resistant mice by implantation of murine retrovirus-infected microglia. J Virol. 1995 Mar;69(3):1408–1419. doi: 10.1128/jvi.69.3.1408-1419.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lynch W. P., Snyder E. Y., Qualtiere L., Portis J. L., Sharpe A. H. Late virus replication events in microglia are required for neurovirulent retrovirus-induced spongiform neurodegeneration: evidence from neural progenitor-derived chimeric mouse brains. J Virol. 1996 Dec;70(12):8896–8907. doi: 10.1128/jvi.70.12.8896-8907.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. McFarlin D. E., Koprowski H. Neurological disorders associated with HTLV-1. Curr Top Microbiol Immunol. 1990;160:100–119. [PubMed] [Google Scholar]
  30. McLean I. W., Nakane P. K. Periodate-lysine-paraformaldehyde fixative. A new fixation for immunoelectron microscopy. J Histochem Cytochem. 1974 Dec;22(12):1077–1083. doi: 10.1177/22.12.1077. [DOI] [PubMed] [Google Scholar]
  31. Murray E. A., Rausch D. M., Lendvay J., Sharer L. R., Eiden L. E. Cognitive and motor impairments associated with SIV infection in rhesus monkeys. Science. 1992 Mar 6;255(5049):1246–1249. doi: 10.1126/science.1546323. [DOI] [PubMed] [Google Scholar]
  32. Navia B. A., Jordan B. D., Price R. W. The AIDS dementia complex: I. Clinical features. Ann Neurol. 1986 Jun;19(6):517–524. doi: 10.1002/ana.410190602. [DOI] [PubMed] [Google Scholar]
  33. Oliff A., Collins L., Mirenda C. Molecular cloning of Friend mink cell focus-inducing virus: identification of mink cell focus-inducing virus-like messages in normal and transformed cells. J Virol. 1983 Nov;48(2):542–546. doi: 10.1128/jvi.48.2.542-546.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Park B. H., Lavi E., Blank K. J., Gaulton G. N. Intracerebral hemorrhages and syncytium formation induced by endothelial cell infection with a murine leukemia virus. J Virol. 1993 Oct;67(10):6015–6024. doi: 10.1128/jvi.67.10.6015-6024.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Phillips T. R., Prospero-Garcia O., Puaoi D. L., Lerner D. L., Fox H. S., Olmsted R. A., Bloom F. E., Henriksen S. J., Elder J. H. Neurological abnormalities associated with feline immunodeficiency virus infection. J Gen Virol. 1994 May;75(Pt 5):979–987. doi: 10.1099/0022-1317-75-5-979. [DOI] [PubMed] [Google Scholar]
  36. Podell M., Oglesbee M., Mathes L., Krakowka S., Olmstead R., Lafrado L. AIDS-associated encephalopathy with experimental feline immunodeficiency virus infection. J Acquir Immune Defic Syndr. 1993 Jul;6(7):758–771. [PubMed] [Google Scholar]
  37. Portis J. L., Czub S., Garon C. F., McAtee F. J. Neurodegenerative disease induced by the wild mouse ecotropic retrovirus is markedly accelerated by long terminal repeat and gag-pol sequences from nondefective Friend murine leukemia virus. J Virol. 1990 Apr;64(4):1648–1656. doi: 10.1128/jvi.64.4.1648-1656.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Portis J. L., Czub S., Robertson S., McAtee F., Chesebro B. Characterization of a neurologic disease induced by a polytropic murine retrovirus: evidence for differential targeting of ecotropic and polytropic viruses in the brain. J Virol. 1995 Dec;69(12):8070–8075. doi: 10.1128/jvi.69.12.8070-8075.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Price R. W., Brew B., Sidtis J., Rosenblum M., Scheck A. C., Cleary P. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science. 1988 Feb 5;239(4840):586–592. doi: 10.1126/science.3277272. [DOI] [PubMed] [Google Scholar]
  40. Pálsson P. A. Maedi and visna in sheep. Front Biol. 1976;44:17–43. [PubMed] [Google Scholar]
  41. Rausch D. M., Heyes M. P., Murray E. A., Lendvay J., Sharer L. R., Ward J. M., Rehm S., Nohr D., Weihe E., Eiden L. E. Cytopathologic and neurochemical correlates of progression to motor/cognitive impairment in SIV-infected rhesus monkeys. J Neuropathol Exp Neurol. 1994 Mar;53(2):165–175. doi: 10.1097/00005072-199403000-00008. [DOI] [PubMed] [Google Scholar]
  42. Rein A. Interference grouping of murine leukemia viruses: a distinct receptor for the MCF-recombinant viruses in mouse cells. Virology. 1982 Jul 15;120(1):251–257. doi: 10.1016/0042-6822(82)90024-1. [DOI] [PubMed] [Google Scholar]
  43. Sharma D. P., Zink M. C., Anderson M., Adams R., Clements J. E., Joag S. V., Narayan O. Derivation of neurotropic simian immunodeficiency virus from exclusively lymphocytetropic parental virus: pathogenesis of infection in macaques. J Virol. 1992 Jun;66(6):3550–3556. doi: 10.1128/jvi.66.6.3550-3556.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sitbon M., Nishio J., Wehrly K., Lodmell D., Chesebro B. Use of a focal immunofluorescence assay on live cells for quantitation of retroviruses: distinction of host range classes in virus mixtures and biological cloning of dual-tropic murine leukemia viruses. Virology. 1985 Feb;141(1):110–118. doi: 10.1016/0042-6822(85)90187-4. [DOI] [PubMed] [Google Scholar]
  45. Sitbon M., Sola B., Evans L., Nishio J., Hayes S. F., Nathanson K., Garon C. F., Chesebro B. Hemolytic anemia and erythroleukemia, two distinct pathogenic effects of Friend MuLV: mapping of the effects to different regions of the viral genome. Cell. 1986 Dec 26;47(6):851–859. doi: 10.1016/0092-8674(86)90800-7. [DOI] [PubMed] [Google Scholar]
  46. Smith M. O., Heyes M. P., Lackner A. A. Early intrathecal events in rhesus macaques (Macaca mulatta) infected with pathogenic or nonpathogenic molecular clones of simian immunodeficiency virus. Lab Invest. 1995 May;72(5):547–558. [PubMed] [Google Scholar]
  47. Springer T., Galfré G., Secher D. S., Milstein C. Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. Eur J Immunol. 1979 Apr;9(4):301–306. doi: 10.1002/eji.1830090410. [DOI] [PubMed] [Google Scholar]
  48. Stephens E. B., Liu Z. Q., Zhu G. W., Adany I., Joag S. V., Foresman L., Berman N. E., Narayan O. Lymphocyte-tropic simian immunodeficiency virus causes persistent infection in the brains of rhesus monkeys. Virology. 1995 Nov 10;213(2):600–614. doi: 10.1006/viro.1995.0032. [DOI] [PubMed] [Google Scholar]
  49. Takahashi K., Wesselingh S. L., Griffin D. E., McArthur J. C., Johnson R. T., Glass J. D. Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol. 1996 Jun;39(6):705–711. doi: 10.1002/ana.410390606. [DOI] [PubMed] [Google Scholar]
  50. Trapp B. D., Bernier L., Andrews S. B., Colman D. R. Cellular and subcellular distribution of 2',3'-cyclic nucleotide 3'-phosphodiesterase and its mRNA in the rat central nervous system. J Neurochem. 1988 Sep;51(3):859–868. doi: 10.1111/j.1471-4159.1988.tb01822.x. [DOI] [PubMed] [Google Scholar]
  51. Wiley C. A., Gardner M. The pathogenesis of murine retroviral infection of the central nervous system. Brain Pathol. 1993 Apr;3(2):123–128. doi: 10.1111/j.1750-3639.1993.tb00736.x. [DOI] [PubMed] [Google Scholar]
  52. Wong P. K. Moloney murine leukemia virus temperature-sensitive mutants: a model for retrovirus-induced neurologic disorders. Curr Top Microbiol Immunol. 1990;160:29–60. doi: 10.1007/978-3-642-75267-4_3. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES