Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Vacuolar myelopathy in transgenic mice expressing human immunodeficiency virus type 1 proteins under the regulation of the myelin basic protein gene promoter

Abstract

Vacuolar myelopathy is a common neurological complication in AIDS patients. The pathogenesis of this spinal cord white matter disease remains unclear and it is still debated whether infection of spinal cord with the human immunodeficiency virus type 1 (HIV–1) is causing the disease. We have generated transgenic mice expressing the entire HIV–1 genome under the regulation of an oligodendrocyte–specific promoter. These mice develop spinal cord vacuolar lesions similar to those found in AIDS patients. This animal model provides in vivo evidence linking the expression of HIV–1 proteins in oligodendrocytes to the spinal cord damage found in vacuolar myelopathy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Goldstick, L., Mandybur, T.I. & Bode, R. Spinal cord degeneration in AIDS. Neurology 35, 103–106 (1985).

    Article  CAS  PubMed  Google Scholar 

  2. Petito, C.K. et al. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 312, 874–879 (1985).

    Article  CAS  PubMed  Google Scholar 

  3. Artigas, J., Grosse, G. & Niedobitek, F. Vacuolar myelopathy in AIDS. A morphological study. Pathol. Res. Pract. 186, 228–237 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Bergmann, M., Gullotta, F., Kuchelmeister, K., Masini, T. & Angeli, G. AIDS-myelopathy: A neuropathological study. Pathol. Res. Pract. 189, 58–65 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Eilbott, D.J. et al. Human immunodeficiency virus type 1 in spinal cords of acquired immunodeficiency syndrome patients with myelopathy: Expression and replication in macrophages. Proc. Natl. Acad. Sci. USA 86, 3337–3341 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Weiser, B. et al. Human immunodeficiency virus type 1 expression in the central nervous system correlates directly with extent of disease. Proc. Natl. Acad. Sci. USA 87, 3997–4001 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tyor, W.R. et al. Cytokine expression of macrophages in HIV-1-associated vacuolar myelopathy. Neurology 43, 1002–1009 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Rosenblum, M. et al. Dissociation of AIDS-related vacuolar myelopathy and productive HIV-1 infection of the spinal cord. Neurology 39, 892–896 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Grafe, M.R. & Wiley, C.A. Spinal cord and peripheral nerve pathology in AIDS: The roles of cytomegalovirus and human immunodeficiency virus. Ann. Neurol. 25, 561–566 (1989).

    Article  CAS  PubMed  Google Scholar 

  10. Hénin, D., Smith, T.W., De Girolami, U., Sughayer, M. & Hauw, J.-J. Neuropathology of the spinal cord in the acquired immunodeficiency syndrome. Hum. Pathol. 23, 1106–1114 (1992).

    Article  PubMed  Google Scholar 

  11. Petito, C.K., Vecchio, D. & Chen, Y.T. HIV antigen and DNA in AIDS spinal cords correlate with macrophage infiltration but not with vacuolar myelopathy. J. Neuropathol. Exp. Neurol. 53, 86–94 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Kamin, S. & Petito, C.K. Idiopathic myelopathies with white matter vacuolation in non-acquired immunodeficiency syndrome patients. Hum. Pathol. 22, 816–824 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Koenig, S. et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233, 1089–1093 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Wiley, C.A., Schrier, R.D., Nelson, J.A., Lampert, P.W. & Oldstone, M.B. Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc. Natl. Acad. Sci. USA 83, 7089–7093 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vazeux, R. et al. AIDS subacute encephalitis: Identification of HIV-infected cells. Am. J. Pathol. 126, 403–410 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Budka, H. & Lassmann, H. Human immunodeficiency virus in glial cells? J. Infect. Dis. 157, 203 (1988).

    Article  Google Scholar 

  17. Sharer, L. & Prineas, J.W. Human immunodeficiency virus in glial cells [continued]? J. Infect. Dis. 157, 204 (1988).

    Article  Google Scholar 

  18. Gosztonyi, G., Artigas, J., Lamperth, L. & Webster, H.D. Human immunodeficiency virus (HIV) distribution in HIV encephalitis: Study of 19 cases with combined use of in situ hybridization and immunocytochemistry. J. Neuropathol. Exp. Neural. 53, 521–534 (1994).

    Article  CAS  Google Scholar 

  19. Nuovo, G.J., Gallery, F., MacConnell, P. & Braun, A. In situ detection of polymerase chain reaction-amplified HIV-1 nucleic acids and tumor necrosis factor-α RNA in the central nervous system. Am. J. Pathol. 144, 659–666 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Korber, B.T. et al. Genetic differences between blood- and brain-derived viral sequences from human immunodeficiency virus type 1-infected patients: Evidence of conserved elements in the V3 region of the envelope protein of brain-derived sequences. J. Virol. 68, 7467–7481 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Gyorkey, F., Melnick, J.L. & Gyorkey, P. Human immunodeficiency virus in brain biopsies of patients with AIDS and progressive encephalopathy. J. Infect. Dis. 155, 870–876 (1987).

    Article  CAS  PubMed  Google Scholar 

  22. Staler, M.H., Eskin, T.A., Benn, S., Angerer, R.C. & Angerer, L.M. Human T-cell lymphotropic virus type HI infection of the central nervous system. A preliminary in situ study. JAMA 256, 2360–2364 (1986).

    Article  Google Scholar 

  23. Pumarola-Sune, T., Navia, B.A., Cordon-Cardo, C., Cho, E.S. & Price, R.W. HIV antigen in the brains of patients with the AIDS dementia complex. Ann. Neural. 21, 490–496 (1987).

    Article  CAS  Google Scholar 

  24. Esiri, M., Morris, C.S. & Miliard, P.R. Fate of oligodendrocytes in HIV-1 infection. AIDS 5, 1081–1088 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Bagasra, O. et al. Cellular reservoirs of HIV-1 in the central nervous system of infected-individuals: Identification by the combination of in situ PCR and immunohistochemistry. AIDS (in the press).

  26. Embretson, J. et al. Analysis of human immunodeficiency virus-infected tissues by amplification and in situ hybridization reveals latent and permissive infections at single-cell resolution. Proc. Natl. Acad. Sci. USA 90, 357–361 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Adachi, A. et al. Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. J. Virol. 59, 284–291 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Katsuki, M. et al. Conversion of normal behavior to shiverer by myelin basic protein antisense cDNA in transgenic mice. Science 241, 593–595 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Allinquant, B., Staugaitis, S.M., D'Urso, D. & Colman, D.R. The ectopic expression of myelin basic protein isoforms in shiverer oligodendrocytes: Implications for myelinogenesis. J. Cell Biol. 113, 393–403 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Yoshioka, T., Feigenbaum, L. & Jay, G. Transgenic mouse model for central nervous system demyelination. Mol. Cell. Biol. 11, 5479–5486 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Turnley, A.M. et al. Dysmyelination in transgenic mice resulting from expression of class I histocompatibility molecules in oligodendrocytes. Nature 353, 566–569 (1991).

    Article  CAS  PubMed  Google Scholar 

  32. Allan, J.S. et al. A new HTLV-III/LAV encoded antigen detected by antibodies from AIDS patients. Science 230, 810–813 (1985).

    Article  CAS  PubMed  Google Scholar 

  33. Arya, S.K. & Gallo, R.C. Three novel genes of human T-lymphotropic virus type III: Immune reactivity of their products with sera from acquired immune deficiency syndrome patients. Proc. Natl. Acad. Sci. USA 83, 2209–2213 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Toggas, S.M. et al. Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367, 188–193 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Saito, Y. et al. Overexpression of Nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissues. Neurology 44, 474–481 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. Tornatore, C., Chandra, R., Berger, J.R. & Major, E.O. HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology 44, 481–487 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Ranki, A. et al. Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia. AIDS 5, 1001–1008 (1995).

    Article  Google Scholar 

  38. Green, R., van Tonder, S.V., Oettle, G.J., Cole, G. & Metz, J. Neurological changes in fruit bats deficient in vitamin B12 . Nature 254, 148–150 (1975).

    Article  CAS  PubMed  Google Scholar 

  39. Scalabrino, G. et al. Subacute combined degeneration in the spinal cords of totally gastrectomized rats. Lab. Invest. 72, 114–123 (1995).

    CAS  PubMed  Google Scholar 

  40. Takahashi, N., Roach, A., Teplow, D.B., Prusiner, S.B. & Hood, L. Cloning and characterization of the myelin basic protein gene from mouse: One gene can encode both 14 kD and 18.5 kD MBPs by alternate use of exons. Cell 42, 139–148 (1985).

    Article  CAS  PubMed  Google Scholar 

  41. Bouchard, L., Lamarre, L., Tremblay, P.J. & Jolicoeur, P. Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57, 931–936 (1989).

    Article  CAS  PubMed  Google Scholar 

  42. Sambrook, J., Frisch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual, 2nd edn. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989).

    Google Scholar 

  43. Chomczynski, P. & Sacchi, N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal. Biochem. 162, 156–159 (1987).

    Article  CAS  PubMed  Google Scholar 

  44. McLean, I.W. & Nakane, P.K. Periodate-lysine-paraformaldehyde fixative. A new fixative for immunoelectron microscopy. J. Histochem. Cytochem. 22, 1077–1083 (1974).

    Article  CAS  PubMed  Google Scholar 

  45. Gravel, C., Kay, D.G. & Jolicoeur, P. Identification of the infected target cell type in spongiform myeloencephalopathy induced by the neurotropic Cas-Br-E murine leukemia virus. J. Virol. 67, 6648–6658 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Jolicoeur, P., Laperrière, A. & Beaulieu, N. Efficient production of human immunodeficiency virus proteins in transgenic mice. J. Virol. 66, 3904–3908 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Thomas, F.P., Chalk, C., Lalonde, R., Robitaille, Y. & Jolicoeur, P. Expression of human immunodeficiency virus type 1 in the nervous system of transgenic mice leads to neurological disease. J. Virol. 68, 7099–7107 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goudreau, G., Carpenter, S., Beaulieu, N. et al. Vacuolar myelopathy in transgenic mice expressing human immunodeficiency virus type 1 proteins under the regulation of the myelin basic protein gene promoter. Nat Med 2, 655–661 (1996). https://doi.org/10.1038/nm0696-655

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0696-655

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing