Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains (original) (raw)

Abstract

We wanted to establish an in vitro human model for AIDS-associated dementia and pursue the hypothesis that this disease process may be a result of soluble factors produced by HIV-infected macrophages. Human brain aggregates were prepared from nine different brain specimens, and were treated with supernatants from in vitro HIV-infected macrophages (SI), uninfected macrophages (SU), infected T cells, or macrophage-conditioned media from four AIDS patients. Seven of nine treated brains exposed to SI showed peripheral rarefaction after 1 wk of incubation that by ultrastructural analysis showed cytoplasmic vacuolation. Aggregates from two of three brain cultures treated with SI for 3 wk became smaller, an approximately 50% decrease in size. The degree of apparent toxicity in brains exposed to patient-derived macrophage supernatants paralleled the proportion of macrophages found to be expressing HIV p24. Ultrastructural abnormalities were not observed in brains treated with supernatants from HIV-infected T cells, uninfected macrophages, or LPS-activated macrophages. Levels of five neurotransmitter amino acids were decreased in comparison to the structural amino acid leucine. These findings suggest that HIV-infected macrophages, infected both in vitro as well as derived from AIDS patients' peripheral blood, produce factors that cause reproducible histochemical, ultrastructural, and functional abnormalities in human brain aggregates.

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  1. Brenneman D. E., Westbrook G. L., Fitzgerald S. P., Ennist D. L., Elkins K. L., Ruff M. R., Pert C. B. Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide. Nature. 1988 Oct 13;335(6191):639–642. doi: 10.1038/335639a0. [DOI] [PubMed] [Google Scholar]
  2. Cheng-Mayer C., Rutka J. T., Rosenblum M. L., McHugh T., Stites D. P., Levy J. A. Human immunodeficiency virus can productively infect cultured human glial cells. Proc Natl Acad Sci U S A. 1987 May;84(10):3526–3530. doi: 10.1073/pnas.84.10.3526. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chiodi F., Fuerstenberg S., Gidlund M., Asjö B., Fenyö E. M. Infection of brain-derived cells with the human immunodeficiency virus. J Virol. 1987 Apr;61(4):1244–1247. doi: 10.1128/jvi.61.4.1244-1247.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Crowe S., Mills J., McGrath M. S. Quantitative immunocytofluorographic analysis of CD4 surface antigen expression and HIV infection of human peripheral blood monocyte/macrophages. AIDS Res Hum Retroviruses. 1987 Summer;3(2):135–145. doi: 10.1089/aid.1987.3.135. [DOI] [PubMed] [Google Scholar]
  5. Faden A. I., Demediuk P., Panter S. S., Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science. 1989 May 19;244(4906):798–800. doi: 10.1126/science.2567056. [DOI] [PubMed] [Google Scholar]
  6. Gonda M. A., Wong-Staal F., Gallo R. C., Clements J. E., Narayan O., Gilden R. V. Sequence homology and morphologic similarity of HTLV-III and visna virus, a pathogenic lentivirus. Science. 1985 Jan 11;227(4683):173–177. doi: 10.1126/science.2981428. [DOI] [PubMed] [Google Scholar]
  7. Gurney M. E., Heinrich S. P., Lee M. R., Yin H. S. Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons. Science. 1986 Oct 31;234(4776):566–574. doi: 10.1126/science.3764429. [DOI] [PubMed] [Google Scholar]
  8. Ho D. D., Rota T. R., Schooley R. T., Kaplan J. C., Allan J. D., Groopman J. E., Resnick L., Felsenstein D., Andrews C. A., Hirsch M. S. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med. 1985 Dec 12;313(24):1493–1497. doi: 10.1056/NEJM198512123132401. [DOI] [PubMed] [Google Scholar]
  9. Hollander H., Levy J. A. Neurologic abnormalities and recovery of human immunodeficiency virus from cerebrospinal fluid. Ann Intern Med. 1987 May;106(5):692–695. doi: 10.7326/0003-4819-106-5-692. [DOI] [PubMed] [Google Scholar]
  10. Koh J. Y., Choi D. W. Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods. 1987 May;20(1):83–90. doi: 10.1016/0165-0270(87)90041-0. [DOI] [PubMed] [Google Scholar]
  11. Kurihara T., Tsukada Y. The regional and subcellular distribution of 2',3'-cyclic nucleotide 3'-phosphohydrolase in the central nervous system. J Neurochem. 1967 Dec;14(12):1167–1174. doi: 10.1111/j.1471-4159.1967.tb06164.x. [DOI] [PubMed] [Google Scholar]
  12. Levy J. A., Shimabukuro J., Hollander H., Mills J., Kaminsky L. Isolation of AIDS-associated retroviruses from cerebrospinal fluid and brain of patients with neurological symptoms. Lancet. 1985 Sep 14;2(8455):586–588. [PubMed] [Google Scholar]
  13. Locksley R. M., Crowe S., Sadick M. D., Heinzel F. P., Gardner K. D., Jr, McGrath M. S., Mills J. Release of interleukin 1 inhibitory activity (contra-IL-1) by human monocyte-derived macrophages infected with human immunodeficiency virus in vitro and in vivo. J Clin Invest. 1988 Dec;82(6):2097–2105. doi: 10.1172/JCI113831. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McGrath M. S., Hwang K. M., Caldwell S. E., Gaston I., Luk K. C., Wu P., Ng V. L., Crowe S., Daniels J., Marsh J. GLQ223: an inhibitor of human immunodeficiency virus replication in acutely and chronically infected cells of lymphocyte and mononuclear phagocyte lineage. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2844–2848. doi: 10.1073/pnas.86.8.2844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McMorris F. A. Cyclic AMP induction of the myelin enzyme 2',3'-cyclic nucleotide 3'-phosphohydrolase in rat oligodendrocytes. J Neurochem. 1983 Aug;41(2):506–515. doi: 10.1111/j.1471-4159.1983.tb04768.x. [DOI] [PubMed] [Google Scholar]
  16. McMorris F. A., Smith T. M., DeSalvo S., Furlanetto R. W. Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development. Proc Natl Acad Sci U S A. 1986 Feb;83(3):822–826. doi: 10.1073/pnas.83.3.822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. McMorris F. A., Smith T. M., Sprinkle T. J., Auszmann J. M. Induction of myelin components: cyclic AMP increases the synthesis rate of 2',3'-cyclic nucleotide 3'-phosphohydrolase in C6 glioma cells. J Neurochem. 1985 Apr;44(4):1242–1251. doi: 10.1111/j.1471-4159.1985.tb08750.x. [DOI] [PubMed] [Google Scholar]
  18. Navia B. A., Cho E. S., Petito C. K., Price R. W. The AIDS dementia complex: II. Neuropathology. Ann Neurol. 1986 Jun;19(6):525–535. doi: 10.1002/ana.410190603. [DOI] [PubMed] [Google Scholar]
  19. Price R. W., Brew B. J. The AIDS dementia complex. J Infect Dis. 1988 Nov;158(5):1079–1083. doi: 10.1093/infdis/158.5.1079. [DOI] [PubMed] [Google Scholar]
  20. Prohaska J. R., Clark D. A., Wells W. W. Improved rapidity and precision in the determination of brain 2',3'-cyclic nucleotide 3'-phosphohydrolase. Anal Biochem. 1973 Nov;56(1):275–282. doi: 10.1016/0003-2697(73)90189-9. [DOI] [PubMed] [Google Scholar]
  21. Pulliam L., Berens M. E., Rosenblum M. L. A normal human brain cell aggregate model for neurobiological studies. J Neurosci Res. 1988 Oct-Dec;21(2-4):521–530. doi: 10.1002/jnr.490210243. [DOI] [PubMed] [Google Scholar]
  22. Shaw G. M., Harper M. E., Hahn B. H., Epstein L. G., Gajdusek D. C., Price R. W., Navia B. A., Petito C. K., O'Hara C. J., Groopman J. E. HTLV-III infection in brains of children and adults with AIDS encephalopathy. Science. 1985 Jan 11;227(4683):177–182. doi: 10.1126/science.2981429. [DOI] [PubMed] [Google Scholar]
  23. Vazeux R., Brousse N., Jarry A., Henin D., Marche C., Vedrenne C., Mikol J., Wolff M., Michon C., Rozenbaum W. AIDS subacute encephalitis. Identification of HIV-infected cells. Am J Pathol. 1987 Mar;126(3):403–410. [PMC free article] [PubMed] [Google Scholar]
  24. Wahl L. M., Corcoran M. L., Pyle S. W., Arthur L. O., Harel-Bellan A., Farrar W. L. Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1. Proc Natl Acad Sci U S A. 1989 Jan;86(2):621–625. doi: 10.1073/pnas.86.2.621. [DOI] [PMC free article] [PubMed] [Google Scholar]