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Mol Med. 1996 July; 2(4): 417–428.
PMCID: PMC2230163

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

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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  • Navia BA, Jordan BD, Price RW. The AIDS dementia complex: I. Clinical features. Ann Neurol. 1986 Jun;19(6):517–524. [PubMed]
  • Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P. The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science. 1988 Feb 5;239(4840):586–592. [PubMed]
  • Vazeux R, Lacroix-Ciaudo C, Blanche S, Cumont MC, 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. [PubMed]
  • Falangola MF, Hanly A, Galvao-Castro B, Petito CK. 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. [PubMed]
  • Falangola MF, Castro-Filho BG, Petito CK. Immune complex deposition in the choroid plexus of patients with acquired immunodeficiency syndrome. Ann Neurol. 1994 Sep;36(3):437–440. [PubMed]
  • Petito CK, Cash KS. 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. [PubMed]
  • Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. [PubMed]
  • Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB. 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. [PubMed]
  • Giulian D, Vaca K, Noonan CA. Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science. 1990 Dec 14;250(4987):1593–1596. [PubMed]
  • Lipton SA. Models of neuronal injury in AIDS: another role for the NMDA receptor? Trends Neurosci. 1992 Mar;15(3):75–79. [PubMed]
  • Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. 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. [PubMed]
  • Dawson VL, Dawson TM, Uhl GR, Snyder SH. 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. [PubMed]
  • Koka P, He K, Camerini D, Tran T, Yashar SS, Merrill JE. 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. [PubMed]
  • Merrill JE, Koyanagi Y, Zack J, Thomas L, Martin F, Chen IS. 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. [PMC free article] [PubMed]
  • Yeung MC, Pulliam L, Lau AS. 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]
  • Griffin DE, Wesselingh SL, McArthur JC. Elevated central nervous system prostaglandins in human immunodeficiency virus-associated dementia. Ann Neurol. 1994 May;35(5):592–597. [PubMed]
  • Wesselingh SL, Power C, Glass JD, Tyor WR, McArthur JC, Farber JM, Griffin JW, Griffin DE. Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol. 1993 Jun;33(6):576–582. [PubMed]
  • Petito CK, Roberts B. Evidence of apoptotic cell death in HIV encephalitis. Am J Pathol. 1995 May;146(5):1121–1130. [PubMed]
  • 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. [PubMed]
  • Gelbard HA, James HJ, Sharer LR, Perry SW, Saito Y, Kazee AM, Blumberg BM, Epstein LG. Apoptotic neurons in brains from paediatric patients with HIV-1 encephalitis and progressive encephalopathy. Neuropathol Appl Neurobiol. 1995 Jun;21(3):208–217. [PubMed]
  • Sharma DP, Zink MC, Anderson M, Adams R, Clements JE, Joag SV, 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. [PMC free article] [PubMed]
  • Anderson MG, Hauer D, Sharma DP, Joag SV, Narayan O, Zink MC, Clements JE. Analysis of envelope changes acquired by SIVmac239 during neuroadaption in rhesus macaques. Virology. 1993 Aug;195(2):616–626. [PubMed]
  • Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. [PMC free article] [PubMed]
  • Mankowski JL, Spelman JP, Ressetar HG, Strandberg JD, Laterra J, Carter DL, Clements JE, Zink MC. 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. [PMC free article] [PubMed]
  • Kent KA, Rud E, Corcoran T, Powell C, Thiriart C, Collignon C, Stott EJ. 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. [PubMed]
  • Seilhean D, Duyckaerts C, Vazeux R, Bolgert F, Brunet P, Katlama C, Gentilini M, Hauw JJ. HIV-1-associated cognitive/motor complex: absence of neuronal loss in the cerebral neocortex. Neurology. 1993 Aug;43(8):1492–1499. [PubMed]
  • Desrosiers RC, Hansen-Moosa A, Mori K, Bouvier DP, King NW, Daniel MD, Ringler DJ. 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. [PubMed]
  • Murray EA, Rausch DM, Lendvay J, Sharer LR, Eiden LE. Cognitive and motor impairments associated with SIV infection in rhesus monkeys. Science. 1992 Mar 6;255(5049):1246–1249. [PubMed]
  • Albina JE, Cui S, Mateo RB, Reichner JS. Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol. 1993 Jun 1;150(11):5080–5085. [PubMed]
  • Ankarcrona M, Dypbukt JM, 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. [PubMed]
  • Talley AK, Dewhurst S, Perry SW, Dollard SC, Gummuluru S, Fine SM, New D, Epstein LG, Gendelman HE, Gelbard HA. 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. [PMC free article] [PubMed]
  • Woods KM, Chapes SK. Three distinct cell phenotypes of induced-TNF cytotoxicity and their relationship to apoptosis. J Leukoc Biol. 1993 Jan;53(1):37–44. [PubMed]
  • Bagetta G, Corasaniti MT, 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. [PubMed]
  • Müller WE, Schröder HC, 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. [PubMed]
  • Groux H, Torpier G, Monté D, Mouton Y, Capron A, Ameisen JC. 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. [PMC free article] [PubMed]
  • Wiley CA, Achim CL. Human immunodeficiency virus encephalitis and dementia. Ann Neurol. 1995 Oct;38(4):559–560. [PubMed]
  • Vaux DL, Haecker G, Strasser A. An evolutionary perspective on apoptosis. Cell. 1994 Mar 11;76(5):777–779. [PubMed]

Articles from Molecular Medicine are provided here courtesy of The Feinstein Institute for Medical Research at North Shore LIJ