• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. May 1995; 146(5): 1121–1130.
PMCID: PMC1869292

Evidence of apoptotic cell death in HIV encephalitis.

Abstract

The mechanism of cell death in the brains of patients with acquired immune deficiency syndrome was examined in 15 cases, 8 of whom had human immunodeficiency virus (HIV) encephalitis, and in 8 control cases. Postmortem formalin-fixed, paraffin-embedded sections were prepared for routine histology and immunohistochemistry to detect cell-specific antigens. Apoptosis was detected by its morphology and by in situ end labeling of its characteristic oligonucleosomal fragments. Combined in situ end labeling and immunohistochemistry identified specific cell types. Six acquired immune deficiency syndrome brains, 5 of which had HIV encephalitis, contained positive nuclei by in situ end labeling. Co-labeling studies identified the cells as neurons, reactive astrocytes, and, rarely, the multinucleated giant cells of HIV encephalitis. The only control with nuclei positive by in situ end labeling had hepatic encephalopathy and Alzheimer type II astrocytes; the location and absence of cell-specific markers suggested a glial origin for the labeled cells. These results demonstrate that at least some neuronal and astrocytic death in HIV infection occurs by apoptosis. Its stimuli are unknown, but likely candidates include tumor necrosis factor or HIV viral products. Additionally, we hypothesize that apoptotic death of reactive astrocytes may be a normal mechanism whereby the brain removes an excess number of astrocytes that have proliferated after certain types of brain injury.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Post MJ, Berger JR, Quencer RM. Asymptomatic and neurologically symptomatic HIV-seropositive individuals: prospective evaluation with cranial MR imaging. Radiology. 1991 Jan;178(1):131–139. [PubMed]
  • Gelman BB, Guinto FC., Jr Morphometry, histopathology, and tomography of cerebral atrophy in the acquired immunodeficiency syndrome. Ann Neurol. 1992 Jul;32(1):31–40. [PubMed]
  • Oster S, Christoffersen P, Gundersen HJ, Nielsen JO, Pakkenberg B, Pedersen C. Cerebral atrophy in AIDS: a stereological study. Acta Neuropathol. 1993;85(6):617–622. [PubMed]
  • Dal Pan GJ, McArthur JH, Aylward E, Selnes OA, Nance-Sproson TE, Kumar AJ, Mellits ED, McArthur JC. Patterns of cerebral atrophy in HIV-1-infected individuals: results of a quantitative MRI analysis. Neurology. 1992 Nov;42(11):2125–2130. [PubMed]
  • Aylward EH, Henderer JD, McArthur JC, Brettschneider PD, Harris GJ, Barta PE, Pearlson GD. Reduced basal ganglia volume in HIV-1-associated dementia: results from quantitative neuroimaging. Neurology. 1993 Oct;43(10):2099–2104. [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]
  • Schmidbauer M, Huemer M, Cristina S, Trabattoni GR, Budka H. Morphological spectrum, distribution and clinical correlation of white matter lesions in AIDS brains. Neuropathol Appl Neurobiol. 1992 Oct;18(5):489–501. [PubMed]
  • Petito CK, Cho ES, Lemann W, Navia BA, Price RW. Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol Exp Neurol. 1986 Nov;45(6):635–646. [PubMed]
  • Ketzler S, Weis S, Haug H, Budka H. Loss of neurons in the frontal cortex in AIDS brains. Acta Neuropathol. 1990;80(1):92–94. [PubMed]
  • Wiley CA, Masliah E, Morey M, Lemere C, DeTeresa R, Grafe M, Hansen L, Terry R. Neocortical damage during HIV infection. Ann Neurol. 1991 Jun;29(6):651–657. [PubMed]
  • Everall IP, Luthert PJ, Lantos PL. Neuronal loss in the frontal cortex in HIV infection. Lancet. 1991 May 11;337(8750):1119–1121. [PubMed]
  • Weis S, Haug H, Budka H. Neuronal damage in the cerebral cortex of AIDS brains: a morphometric study. Acta Neuropathol. 1993;85(2):185–189. [PubMed]
  • Masliah E, Achim CL, Ge N, DeTeresa R, Terry RD, Wiley CA. Spectrum of human immunodeficiency virus-associated neocortical damage. Ann Neurol. 1992 Sep;32(3):321–329. [PubMed]
  • Gelman BB. Diffuse microgliosis associated with cerebral atrophy in the acquired immunodeficiency syndrome. Ann Neurol. 1993 Jul;34(1):65–70. [PubMed]
  • Weis S, Haug H, Budka H. Astroglial changes in the cerebral cortex of AIDS brains: a morphometric and immunohistochemical investigation. Neuropathol Appl Neurobiol. 1993 Aug;19(4):329–335. [PubMed]
  • Ciardi A, Sinclair E, Scaravilli F, Harcourt-Webster NJ, Lucas S. The involvement of the cerebral cortex in human immunodeficiency virus encephalopathy: a morphological and immunohistochemical study. Acta Neuropathol. 1990;81(1):51–59. [PubMed]
  • Petito CK. What causes brain atrophy in human immunodeficiency virus infection? Ann Neurol. 1993 Aug;34(2):128–129. [PubMed]
  • Selmaj K, Raine CS, Farooq M, Norton WT, Brosnan CF. Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J Immunol. 1991 Sep 1;147(5):1522–1529. [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]
  • Gagliardini V, Fernandez PA, Lee RK, Drexler HC, Rotello RJ, Fishman MC, Yuan J. Prevention of vertebrate neuronal death by the crmA gene. Science. 1994 Feb 11;263(5148):826–828. [PubMed]
  • Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell. 1986 Mar 28;44(6):817–829. [PubMed]
  • Wyllie AH, Kerr JF, Currie AR. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. [PubMed]
  • Ameisen JC. Programmed cell death and AIDS: from hypothesis to experiment. Immunol Today. 1992 Oct;13(10):388–391. [PubMed]
  • Gougeon ML, Montagnier L. Apoptosis in AIDS. Science. 1993 May 28;260(5112):1269–1270. [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]
  • Wijsman JH, Jonker RR, Keijzer R, van de Velde CJ, Cornelisse CJ, van Dierendonck JH. A new method to detect apoptosis in paraffin sections: in situ end-labeling of fragmented DNA. J Histochem Cytochem. 1993 Jan;41(1):7–12. [PubMed]
  • Kerr JF. A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J Pathol Bacteriol. 1965 Oct;90(2):419–435. [PubMed]
  • Leoncini L, Del Vecchio MT, Megha T, Barbini P, Galieni P, Pileri S, Sabattini E, Gherlinzoni F, Tosi P, Kraft R, et al. Correlations between apoptotic and proliferative indices in malignant non-Hodgkin's lymphomas. Am J Pathol. 1993 Mar;142(3):755–763. [PMC free article] [PubMed]
  • Harmon BV, Corder AM, Collins RJ, Gobé GC, Allen J, Allan DJ, Kerr JF. Cell death induced in a murine mastocytoma by 42-47 degrees C heating in vitro: evidence that the form of death changes from apoptosis to necrosis above a critical heat load. Int J Radiat Biol. 1990 Nov;58(5):845–858. [PubMed]
  • Raff MC, Barres BA, Burne JF, Coles HS, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 1993 Oct 29;262(5134):695–700. [PubMed]
  • D'Mello SR, Galli C, Ciotti T, Calissano P. Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10989–10993. [PMC free article] [PubMed]
  • Mailhos C, Howard MK, Latchman DS. Heat shock protects neuronal cells from programmed cell death by apoptosis. Neuroscience. 1993 Aug;55(3):621–627. [PubMed]
  • Tominaga T, Kure S, Narisawa K, Yoshimoto T. Endonuclease activation following focal ischemic injury in the rat brain. Brain Res. 1993 Apr 9;608(1):21–26. [PubMed]
  • Ferrer I, Tortosa A, Macaya A, Sierra A, Moreno D, Munell F, Blanco R, Squier W. Evidence of nuclear DNA fragmentation following hypoxia-ischemia in the infant rat brain, and transient forebrain ischemia in the adult gerbil. Brain Pathol. 1994 Apr;4(2):115–122. [PubMed]
  • Deshpande J, Bergstedt K, Lindén T, Kalimo H, Wieloch T. Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death. Exp Brain Res. 1992;88(1):91–105. [PubMed]
  • Pender MP, Nguyen KB, McCombe PA, Kerr JF. Apoptosis in the nervous system in experimental allergic encephalomyelitis. J Neurol Sci. 1991 Jul;104(1):81–87. [PubMed]
  • Schmied M, Breitschopf H, Gold R, Zischler H, Rothe G, Wekerle H, Lassmann H. Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. Am J Pathol. 1993 Aug;143(2):446–452. [PMC free article] [PubMed]
  • Umehara F, Nakamura A, Izumo S, Kubota R, Ijichi S, Kashio N, Hashimoto K, Usuku K, Sato E, Osame M. Apoptosis of T lymphocytes in the spinal cord lesions in HTLV-I-associated myelopathy: a possible mechanism to control viral infection in the central nervous system. J Neuropathol Exp Neurol. 1994 Nov;53(6):617–624. [PubMed]
  • Gold R, Schmied M, Rothe G, Zischler H, Breitschopf H, Wekerle H, Lassmann H. Detection of DNA fragmentation in apoptosis: application of in situ nick translation to cell culture systems and tissue sections. J Histochem Cytochem. 1993 Jul;41(7):1023–1030. [PubMed]
  • Migheli A, Cavalla P, Marino S, Schiffer D. A study of apoptosis in normal and pathologic nervous tissue after in situ end-labeling of DNA strand breaks. J Neuropathol Exp Neurol. 1994 Nov;53(6):606–616. [PubMed]
  • Barres BA. New roles for glia. J Neurosci. 1991 Dec;11(12):3685–3694. [PubMed]
  • Hansson E. Astroglia from defined brain regions as studied with primary cultures. Prog Neurobiol. 1988;30(5):369–397. [PubMed]
  • Sharer LR. Pathology of HIV-1 infection of the central nervous system. A review. J Neuropathol Exp Neurol. 1992 Jan;51(1):3–11. [PubMed]
  • Petito CK, Morgello S, Felix JC, Lesser ML. The two patterns of reactive astrocytosis in postischemic rat brain. J Cereb Blood Flow Metab. 1990 Nov;10(6):850–859. [PubMed]
  • Tyor WR, Glass JD, Griffin JW, Becker PS, McArthur JC, Bezman L, Griffin DE. Cytokine expression in the brain during the acquired immunodeficiency syndrome. Ann Neurol. 1992 Apr;31(4):349–360. [PubMed]
  • Odeh M. The role of tumour necrosis factor-alpha in acquired immunodeficiency syndrome. J Intern Med. 1990 Dec;228(6):549–556. [PubMed]
  • Grimaldi LM, Martino GV, Franciotta DM, Brustia R, Castagna A, Pristerà R, Lazzarin A. Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann Neurol. 1991 Jan;29(1):21–25. [PubMed]
  • Goudsmit J, Epstein LG, Paul DA, van der Helm HJ, Dawson GJ, Asher DM, Yanagihara R, Wolff AV, Gibbs CJ, Jr, Gajdusek DC. Intra-blood-brain barrier synthesis of human immunodeficiency virus antigen and antibody in humans and chimpanzees. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3876–3880. [PMC free article] [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]
  • Power C, Kong PA, Crawford TO, Wesselingh S, Glass JD, McArthur JC, Trapp BD. Cerebral white matter changes in acquired immunodeficiency syndrome dementia: alterations of the blood-brain barrier. Ann Neurol. 1993 Sep;34(3):339–350. [PubMed]
  • Kaiser PK, Offermann JT, Lipton SA. Neuronal injury due to HIV-1 envelope protein is blocked by anti-gp120 antibodies but not by anti-CD4 antibodies. Neurology. 1990 Nov;40(11):1757–1761. [PubMed]
  • Brenneman DE, Westbrook GL, Fitzgerald SP, Ennist DL, Elkins KL, Ruff MR, Pert CB. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature. 1988 Oct 13;335(6191):639–642. [PubMed]
  • Pulliam L, West D, Haigwood N, Swanson RA. HIV-1 envelope gp120 alters astrocytes in human brain cultures. AIDS Res Hum Retroviruses. 1993 May;9(5):439–444. [PubMed]
  • Dreyer EB, Kaiser PK, Offermann JT, Lipton SA. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science. 1990 Apr 20;248(4953):364–367. [PubMed]
  • Selmaj KW, Raine CS. Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol. 1988 Apr;23(4):339–346. [PubMed]
  • Allsopp TE, Wyatt S, Paterson HF, Davies AM. The proto-oncogene bcl-2 can selectively rescue neurotrophic factor-dependent neurons from apoptosis. Cell. 1993 Apr 23;73(2):295–307. [PubMed]
  • Kane DJ, Sarafian TA, Anton R, Hahn H, Gralla EB, Valentine JS, Ord T, Bredesen DE. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. [PubMed]
  • Howard MK, Burke LC, Mailhos C, Pizzey A, Gilbert CS, Lawson WD, Collins MK, Thomas NS, Latchman DS. Cell cycle arrest of proliferating neuronal cells by serum deprivation can result in either apoptosis or differentiation. J Neurochem. 1993 May;60(5):1783–1791. [PubMed]
  • Pittman RN, Wang S, DiBenedetto AJ, Mills JC. A system for characterizing cellular and molecular events in programmed neuronal cell death. J Neurosci. 1993 Sep;13(9):3669–3680. [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...