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. 1996 Jul;2(4):417–428.

Neurovirulent simian immunodeficiency virus infection induces neuronal, endothelial, and glial apoptosis.

D C Adamson 1, T M Dawson 1, M C Zink 1, J E Clements 1, V L Dawson 1
PMCID: PMC2230163  PMID: 8827712

Abstract

BACKGROUND: Studies of human immunodeficiency virus type 1 (HIV-1) associated dementia have shown neuronal loss in discrete areas. The presence and mechanism of neuronal death, however, has remained quite elusive. One mechanism of cell death, apoptosis, has been clearly demonstrated outside the central nervous system (CNS) in HIV-1 infection but has not been firmly established within the CNS. Therefore, we set out to ascertain whether neuronal cell loss in simian immunodeficiency virus (SIV) encephalitis, an animal model of HIV-1-associated dementia, is a result of apoptosis. MATERIALS AND METHODS: With the aid of an in situ technique for identifying the 3'-OH ends of newly fragmented DNA characteristic of apoptosis, in conjunction with specific detected morphological criteria via light microscopy, we have examined encephalitic and nonencephalitic brains of macaques infected with a neurovirulent, neuroendotheliotropic strain of SIV to see if virus is spatially associated with apoptosis of neurons and non-neuronal cell types. RESULTS: We demonstrate the presence of DNA damage, indicative of apoptosis, in neurons, endothelial cells, and glial cells of the CNS of SIV-infected macaques. Furthermore, we observe an association between the localization of cells with significant DNA fragmentation and perivascular inflammatory cell infiltrates containing SIV-infected macrophages and multinucleated giant cells. Quantitative analysis reveals significantly more cells with DNA fragmentation in the CNS of macaques infected with neurovirulent, neuroendotheliotropic SIV strains as compared with strictly lymphocyte-tropic SIV strains and SIV negative controls. CONCLUSIONS: Our findings of apoptosis in SIV-infected CNS may potentially lead to a better understanding of the AIDS dementia complex, ultimately providing a basis for better treatments.

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Selected References

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

  1. Adle-Biassette H., Levy Y., Colombel M., Poron F., Natchev S., Keohane C., Gray F. Neuronal apoptosis in HIV infection in adults. Neuropathol Appl Neurobiol. 1995 Jun;21(3):218–227. doi: 10.1111/j.1365-2990.1995.tb01053.x. [DOI] [PubMed] [Google Scholar]
  2. Albina J. E., Cui S., Mateo R. B., Reichner J. S. Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol. 1993 Jun 1;150(11):5080–5085. [PubMed] [Google Scholar]
  3. 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]
  4. Ankarcrona M., Dypbukt J. M., Brüne B., Nicotera P. Interleukin-1 beta-induced nitric oxide production activates apoptosis in pancreatic RINm5F cells. Exp Cell Res. 1994 Jul;213(1):172–177. doi: 10.1006/excr.1994.1187. [DOI] [PubMed] [Google Scholar]
  5. Bagetta G., Corasaniti M. T., Berliocchi L., Navarra M., Finazzi-Agrò A., Nisticò G. HIV-1 gp120 produces DNA fragmentation in the cerebral cortex of rat. Biochem Biophys Res Commun. 1995 Jun 6;211(1):130–136. doi: 10.1006/bbrc.1995.1787. [DOI] [PubMed] [Google Scholar]
  6. Bonfoco E., Krainc D., Ankarcrona M., Nicotera P., Lipton S. A. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162–7166. doi: 10.1073/pnas.92.16.7162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dawson V. L., Dawson T. M., Uhl G. R., Snyder S. H. Human immunodeficiency virus type 1 coat protein neurotoxicity mediated by nitric oxide in primary cortical cultures. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3256–3259. doi: 10.1073/pnas.90.8.3256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Falangola M. F., Castro-Filho B. G., Petito C. K. Immune complex deposition in the choroid plexus of patients with acquired immunodeficiency syndrome. Ann Neurol. 1994 Sep;36(3):437–440. doi: 10.1002/ana.410360316. [DOI] [PubMed] [Google Scholar]
  10. Falangola M. F., Hanly A., Galvao-Castro B., Petito C. K. HIV infection of human choroid plexus: a possible mechanism of viral entry into the CNS. J Neuropathol Exp Neurol. 1995 Jul;54(4):497–503. doi: 10.1097/00005072-199507000-00003. [DOI] [PubMed] [Google Scholar]
  11. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gelbard H. A., James H. J., Sharer L. R., Perry S. W., Saito Y., Kazee A. M., Blumberg B. M., Epstein L. G. Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy. Neuropathol Appl Neurobiol. 1995 Jun;21(3):208–217. doi: 10.1111/j.1365-2990.1995.tb01052.x. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. Griffin D. E., Wesselingh S. L., McArthur J. C. Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann Neurol. 1994 May;35(5):592–597. doi: 10.1002/ana.410350513. [DOI] [PubMed] [Google Scholar]
  15. Groux H., Torpier G., Monté D., Mouton Y., Capron A., Ameisen J. C. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992 Feb 1;175(2):331–340. doi: 10.1084/jem.175.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kent K. A., Rud E., Corcoran T., Powell C., Thiriart C., Collignon C., Stott E. J. Identification of two neutralizing and 8 non-neutralizing epitopes on simian immunodeficiency virus envelope using monoclonal antibodies. AIDS Res Hum Retroviruses. 1992 Jun;8(6):1147–1151. doi: 10.1089/aid.1992.8.1147. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Koka P., He K., Camerini D., Tran T., Yashar S. S., Merrill J. E. The mapping of HIV-1 gp160 epitopes required for interleukin-1 and tumor necrosis factor alpha production in glial cells. J Neuroimmunol. 1995 Mar;57(1-2):179–191. doi: 10.1016/0165-5728(94)00184-p. [DOI] [PubMed] [Google Scholar]
  19. Lipton S. A. Models of neuronal injury in AIDS: another role for the NMDA receptor? Trends Neurosci. 1992 Mar;15(3):75–79. doi: 10.1016/0166-2236(92)90013-x. [DOI] [PubMed] [Google Scholar]
  20. Mankowski J. L., Spelman J. P., Ressetar H. G., Strandberg J. D., Laterra J., Carter D. L., Clements J. E., Zink M. C. Neurovirulent simian immunodeficiency virus replicates productively in endothelial cells of the central nervous system in vivo and in vitro. J Virol. 1994 Dec;68(12):8202–8208. doi: 10.1128/jvi.68.12.8202-8208.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Merrill J. E., Koyanagi Y., Zack J., Thomas L., Martin F., Chen I. S. Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human immunodeficiency virus type 1. J Virol. 1992 Apr;66(4):2217–2225. doi: 10.1128/jvi.66.4.2217-2225.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Müller W. E., Schröder H. C., Ushijima H., Dapper J., Bormann J. gp120 of HIV-1 induces apoptosis in rat cortical cell cultures: prevention by memantine. Eur J Pharmacol. 1992 Jul 1;226(3):209–214. doi: 10.1016/0922-4106(92)90063-2. [DOI] [PubMed] [Google Scholar]
  24. 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]
  25. Petito C. K., Cash K. S. Blood-brain barrier abnormalities in the acquired immunodeficiency syndrome: immunohistochemical localization of serum proteins in postmortem brain. Ann Neurol. 1992 Nov;32(5):658–666. doi: 10.1002/ana.410320509. [DOI] [PubMed] [Google Scholar]
  26. Petito C. K., Roberts B. Evidence of apoptotic cell death in HIV encephalitis. Am J Pathol. 1995 May;146(5):1121–1130. [PMC free article] [PubMed] [Google Scholar]
  27. 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]
  28. Seilhean D., Duyckaerts C., Vazeux R., Bolgert F., Brunet P., Katlama C., Gentilini M., Hauw J. J. HIV-1-associated cognitive/motor complex: absence of neuronal loss in the cerebral neocortex. Neurology. 1993 Aug;43(8):1492–1499. doi: 10.1212/wnl.43.8.1492. [DOI] [PubMed] [Google Scholar]
  29. 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]
  30. Talley A. K., Dewhurst S., Perry S. W., Dollard S. C., Gummuluru S., Fine S. M., New D., Epstein L. G., Gendelman H. E., Gelbard H. A. Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA. Mol Cell Biol. 1995 May;15(5):2359–2366. doi: 10.1128/mcb.15.5.2359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Vaux D. L., Haecker G., Strasser A. An evolutionary perspective on apoptosis. Cell. 1994 Mar 11;76(5):777–779. doi: 10.1016/0092-8674(94)90350-6. [DOI] [PubMed] [Google Scholar]
  32. Vazeux R., Lacroix-Ciaudo C., Blanche S., Cumont M. C., Henin D., Gray F., Boccon-Gibod L., Tardieu M. Low levels of human immunodeficiency virus replication in the brain tissue of children with severe acquired immunodeficiency syndrome encephalopathy. Am J Pathol. 1992 Jan;140(1):137–144. [PMC free article] [PubMed] [Google Scholar]
  33. Wesselingh S. L., Power C., Glass J. D., Tyor W. R., McArthur J. C., Farber J. M., Griffin J. W., Griffin D. E. Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol. 1993 Jun;33(6):576–582. doi: 10.1002/ana.410330604. [DOI] [PubMed] [Google Scholar]
  34. Wiley C. A., Achim C. L. Human immunodeficiency virus encephalitis and dementia. Ann Neurol. 1995 Oct;38(4):559–560. doi: 10.1002/ana.410380402. [DOI] [PubMed] [Google Scholar]
  35. 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]
  36. Woods K. M., Chapes S. K. Three distinct cell phenotypes of induced-TNF cytotoxicity and their relationship to apoptosis. J Leukoc Biol. 1993 Jan;53(1):37–44. doi: 10.1002/jlb.53.1.37. [DOI] [PubMed] [Google Scholar]
  37. Yeung M. C., Pulliam L., Lau A. S. The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-alpha. AIDS. 1995 Feb;9(2):137–143. [PubMed] [Google Scholar]

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