Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Aug;71(8):6055–6060. doi: 10.1128/jvi.71.8.6055-6060.1997

Pathogenesis of simian immunodeficiency virus encephalitis: viral determinants of neurovirulence.

J L Mankowski 1, M T Flaherty 1, J P Spelman 1, D A Hauer 1, P J Didier 1, A M Amedee 1, M Murphey-Corb 1, L M Kirstein 1, A Muñoz 1, J E Clements 1, M C Zink 1
PMCID: PMC191864  PMID: 9223498

Abstract

To examine the relationship between macrophage tropism and neurovirulence, macaques were inoculated with two recombinant hybrid viruses derived from the parent viruses SIVmac239, a lymphocyte-tropic, non-neurovirulent clone, and SIV/17E-Br, a macrophage-tropic, neurovirulent virus strain. The first recombinant, SIV/17E-Cl, contained the portion of the env gene that encodes the surface glycoprotein and a short segment of the transmembrane glycoprotein of SIV/17E-Br in the backbone of SIVmac239. Unlike SIVmac239, SIV/17E-Cl replicated productively in macrophages, demonstrating that sequences in the surface portion of env determine macrophage tropism. None of five macaques inoculated with SIV/17E-Cl developed simian immunodeficiency virus (SIV) encephalitis. The second recombinant, SIV/17E-Fr, which contained the entire env and nef genes and the 3' long terminal repeat of SIV/17E-Br in the SIVmac239 backbone, was also macrophage tropic. Six of nine macaques inoculated with SIV/17E-Fr developed SIV encephalitis ranging from mild to moderate in severity, indicating a significant (P = 0.031) difference in the neurovirulence of the two recombinants. In both groups of macaques, CD4+ cell counts declined gradually during infection and there was no significant difference in the rate of the decline between the two groups of macaques. This study demonstrated that macrophage tropism alone is not sufficient for the development of neurological disease. In addition, it showed that while sequences in the surface portion of the envelope gene determine macrophage tropism, additional sequences derived from the transmembrane portion of envelope and/or nef confer neurovirulence.

Full Text

The Full Text of this article is available as a PDF (344.4 KB).

Selected References

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

  1. Anderson M. G., Hauer D., Sharma D. P., Joag S. V., Narayan O., Zink M. C., Clements J. E. Analysis of envelope changes acquired by SIVmac239 during neuroadaption in rhesus macaques. Virology. 1993 Aug;195(2):616–626. doi: 10.1006/viro.1993.1413. [DOI] [PubMed] [Google Scholar]
  2. Brinkmann R., Schwinn A., Narayan O., Zink C., Kreth H. W., Roggendorf W., Dörries R., Schwender S., Imrich H., ter Meulen V. Human immunodeficiency virus infection in microglia: correlation between cells infected in the brain and cells cultured from infectious brain tissue. Ann Neurol. 1992 Apr;31(4):361–365. doi: 10.1002/ana.410310403. [DOI] [PubMed] [Google Scholar]
  3. Cserr H. F. Role of secretion and bulk flow of brain interstitial fluid in brain volume regulation. Ann N Y Acad Sci. 1988;529:9–20. doi: 10.1111/j.1749-6632.1988.tb51415.x. [DOI] [PubMed] [Google Scholar]
  4. Desrosiers R. C., Hansen-Moosa A., Mori K., Bouvier D. P., King N. W., Daniel M. D., Ringler D. J. Macrophage-tropic variants of SIV are associated with specific AIDS-related lesions but are not essential for the development of AIDS. Am J Pathol. 1991 Jul;139(1):29–35. [PMC free article] [PubMed] [Google Scholar]
  5. Flaherty M. T., Hauer D. A., Mankowski J. L., Zink M. C., Clements J. E. Molecular and biological characterization of a neurovirulent molecular clone of simian immunodeficiency virus. J Virol. 1997 Aug;71(8):5790–5798. doi: 10.1128/jvi.71.8.5790-5798.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Goodenow M., Huet T., Saurin W., Kwok S., Sninsky J., Wain-Hobson S. HIV-1 isolates are rapidly evolving quasispecies: evidence for viral mixtures and preferred nucleotide substitutions. J Acquir Immune Defic Syndr. 1989;2(4):344–352. [PubMed] [Google Scholar]
  7. Irani D. N., Griffin D. E. Regulation of lymphocyte homing into the brain during viral encephalitis at various stages of infection. J Immunol. 1996 May 15;156(10):3850–3857. [PubMed] [Google Scholar]
  8. Kodama T., Mori K., Kawahara T., Ringler D. J., Desrosiers R. C. Analysis of simian immunodeficiency virus sequence variation in tissues of rhesus macaques with simian AIDS. J Virol. 1993 Nov;67(11):6522–6534. doi: 10.1128/jvi.67.11.6522-6534.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Koyanagi Y., Miles S., Mitsuyasu R. T., Merrill J. E., Vinters H. V., Chen I. S. Dual infection of the central nervous system by AIDS viruses with distinct cellular tropisms. Science. 1987 May 15;236(4803):819–822. doi: 10.1126/science.3646751. [DOI] [PubMed] [Google Scholar]
  10. Lackner A. A., Smith M. O., Munn R. J., Martfeld D. J., Gardner M. B., Marx P. A., Dandekar S. Localization of simian immunodeficiency virus in the central nervous system of rhesus monkeys. Am J Pathol. 1991 Sep;139(3):609–621. [PMC free article] [PubMed] [Google Scholar]
  11. Martin L. N., Murphey-Corb M., Soike K. F., Davison-Fairburn B., Baskin G. B. Effects of initiation of 3'-azido,3'-deoxythymidine (zidovudine) treatment at different times after infection of rhesus monkeys with simian immunodeficiency virus. J Infect Dis. 1993 Oct;168(4):825–835. doi: 10.1093/infdis/168.4.825. [DOI] [PubMed] [Google Scholar]
  12. McArthur J. C., Hoover D. R., Bacellar H., Miller E. N., Cohen B. A., Becker J. T., Graham N. M., McArthur J. H., Selnes O. A., Jacobson L. P. Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology. 1993 Nov;43(11):2245–2252. doi: 10.1212/wnl.43.11.2245. [DOI] [PubMed] [Google Scholar]
  13. McArthur J. C., Selnes O. A., Glass J. D., Hoover D. R., Bacellar H. HIV dementia. Incidence and risk factors. Res Publ Assoc Res Nerv Ment Dis. 1994;72:251–272. [PubMed] [Google Scholar]
  14. Mori K., Ringler D. J., Kodama T., Desrosiers R. C. Complex determinants of macrophage tropism in env of simian immunodeficiency virus. J Virol. 1992 Apr;66(4):2067–2075. doi: 10.1128/jvi.66.4.2067-2075.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. Price R. W. Neurological complications of HIV infection. Lancet. 1996 Aug 17;348(9025):445–452. doi: 10.1016/S0140-6736(95)11035-6. [DOI] [PubMed] [Google Scholar]
  18. Ringler D. J., Hunt R. D., Desrosiers R. C., Daniel M. D., Chalifoux L. V., King N. W. Simian immunodeficiency virus-induced meningoencephalitis: natural history and retrospective study. Ann Neurol. 1988;23 (Suppl):S101–S107. doi: 10.1002/ana.410230726. [DOI] [PubMed] [Google Scholar]
  19. Sharer L. R., Baskin G. B., Cho E. S., Murphey-Corb M., Blumberg B. M., Epstein L. G. Comparison of simian immunodeficiency virus and human immunodeficiency virus encephalitides in the immature host. Ann Neurol. 1988;23 (Suppl):S108–S112. doi: 10.1002/ana.410230727. [DOI] [PubMed] [Google Scholar]
  20. Sharer L. R., Michaels J., Murphey-Corb M., Hu F. S., Kuebler D. J., Martin L. N., Baskin G. B. Serial pathogenesis study of SIV brain infection. J Med Primatol. 1991 Jun;20(4):211–217. [PubMed] [Google Scholar]
  21. 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]
  22. 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 U S A. 1986 Sep;83(18):7089–7093. doi: 10.1073/pnas.83.18.7089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Zink M. C., Yager J. A., Myers J. D. Pathogenesis of caprine arthritis encephalitis virus. Cellular localization of viral transcripts in tissues of infected goats. Am J Pathol. 1990 Apr;136(4):843–854. [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES