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. 1992 Apr;66(4):2217–2225. doi: 10.1128/jvi.66.4.2217-2225.1992

Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human immunodeficiency virus type 1.

J E Merrill 1, Y Koyanagi 1, J Zack 1, L Thomas 1, F Martin 1, I S Chen 1
PMCID: PMC289014  PMID: 1548758

Abstract

Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha) are produced by leukocytes and play a role in immune responses. They also function in normal brain physiology as well as in pathological conditions within the central nervous system, where they are produced by brain macrophages (microglia) and brain astrocytes. In this study, we document the ability of human immunodeficiency virus type 1 (HIV-1) to induce TNF alpha and IL-1 in primary rat brain cultures. While productive infection did not occur in these cells, it was not required for cytokine induction. Using monocyte/macrophage-tropic (JRFL) and T-cell-tropic (IIIB) strains of HIV-1, we were able to induce cytokines in both microglia and astrocytes. In addition to whole virus, recombinant envelope proteins also induced these cytokines. The induction of IL-1 and TNF alpha could be blocked by a panel of antibodies recognizing epitopes in the gp120 and gp41 areas of the envelope. Soluble recombinant CD4 did not block TNF alpha and IL-1 production. If TNF alpha and IL-1 can be induced in brain tissue by HIV-1, they may contribute to some of the neurologic disorders associated with AIDS.

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Selected References

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

  1. Aggarwal B. B., Kohr W. J., Hass P. E., Moffat B., Spencer S. A., Henzel W. J., Bringman T. S., Nedwin G. E., Goeddel D. V., Harkins R. N. Human tumor necrosis factor. Production, purification, and characterization. J Biol Chem. 1985 Feb 25;260(4):2345–2354. [PubMed] [Google Scholar]
  2. Benveniste E. N., Sparacio S. M., Bethea J. R. Tumor necrosis factor-alpha enhances interferon-gamma-mediated class II antigen expression on astrocytes. J Neuroimmunol. 1989 Dec;25(2-3):209–219. doi: 10.1016/0165-5728(89)90139-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Brown S. L., Smith L. R., Blalock J. E. Interleukin 1 and interleukin 2 enhance proopiomelanocortin gene expression in pituitary cells. J Immunol. 1987 Nov 15;139(10):3181–3183. [PubMed] [Google Scholar]
  5. 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]
  6. Chesebro B., Buller R., Portis J., Wehrly K. Failure of human immunodeficiency virus entry and infection in CD4-positive human brain and skin cells. J Virol. 1990 Jan;64(1):215–221. doi: 10.1128/jvi.64.1.215-221.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. Clapham P. R., Weber J. N., Whitby D., McIntosh K., Dalgleish A. G., Maddon P. J., Deen K. C., Sweet R. W., Weiss R. A. Soluble CD4 blocks the infectivity of diverse strains of HIV and SIV for T cells and monocytes but not for brain and muscle cells. Nature. 1989 Jan 26;337(6205):368–370. doi: 10.1038/337368a0. [DOI] [PubMed] [Google Scholar]
  9. Clark S. J., Jefferies W. A., Barclay A. N., Gagnon J., Williams A. F. Peptide and nucleotide sequences of rat CD4 (W3/25) antigen: evidence for derivation from a structure with four immunoglobulin-related domains. Proc Natl Acad Sci U S A. 1987 Mar;84(6):1649–1653. doi: 10.1073/pnas.84.6.1649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Conlon P. J. A rapid biologic assay for the detection of interleukin 1. J Immunol. 1983 Sep;131(3):1280–1282. [PubMed] [Google Scholar]
  11. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dreyer E. B., Kaiser P. K., Offermann J. T., Lipton S. A. HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science. 1990 Apr 20;248(4953):364–367. doi: 10.1126/science.2326646. [DOI] [PubMed] [Google Scholar]
  13. Durda P. J., Leece B., Jenoski A., Rabin H., Fisher A., Wong-Staal F. Characterization of murine monoclonal antibodies to HIV-1 induced by synthetic peptides. AIDS Res Hum Retroviruses. 1988 Oct;4(5):331–342. doi: 10.1089/aid.1988.4.331. [DOI] [PubMed] [Google Scholar]
  14. Farrar W. L., Kilian P. L., Ruff M. R., Hill J. M., Pert C. B. Visualization and characterization of interleukin 1 receptors in brain. J Immunol. 1987 Jul 15;139(2):459–463. [PubMed] [Google Scholar]
  15. Frei K., Siepl C., Groscurth P., Bodmer S., Schwerdel C., Fontana A. Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microglial cells. Eur J Immunol. 1987 Sep;17(9):1271–1278. doi: 10.1002/eji.1830170909. [DOI] [PubMed] [Google Scholar]
  16. Funke I., Hahn A., Rieber E. P., Weiss E., Riethmüller G. The cellular receptor (CD4) of the human immunodeficiency virus is expressed on neurons and glial cells in human brain. J Exp Med. 1987 Apr 1;165(4):1230–1235. doi: 10.1084/jem.165.4.1230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gabuzda D. H., Hirsch M. S. Neurologic manifestations of infection with human immunodeficiency virus. Clinical features and pathogenesis. Ann Intern Med. 1987 Sep;107(3):383–391. doi: 10.7326/0003-4819-107-2-383. [DOI] [PubMed] [Google Scholar]
  18. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  19. Giulian D., Baker T. J., Shih L. C., Lachman L. B. Interleukin 1 of the central nervous system is produced by ameboid microglia. J Exp Med. 1986 Aug 1;164(2):594–604. doi: 10.1084/jem.164.2.594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Giulian D., Woodward J., Young D. G., Krebs J. F., Lachman L. B. Interleukin-1 injected into mammalian brain stimulates astrogliosis and neovascularization. J Neurosci. 1988 Jul;8(7):2485–2490. doi: 10.1523/JNEUROSCI.08-07-02485.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gorny M. K., Gianakakos V., Sharpe S., Zolla-Pazner S. Generation of human monoclonal antibodies to human immunodeficiency virus. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1624–1628. doi: 10.1073/pnas.86.5.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gosting L. H., McClure J., Dickinson E. S., Watanabe S. M., Shriver K., Goldstein L. C. Monoclonal antibodies to gp110 and gp41 of human immunodeficiency virus. J Clin Microbiol. 1987 May;25(5):845–848. doi: 10.1128/jcm.25.5.845-848.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Grau G. E., Fajardo L. F., Piguet P. F., Allet B., Lambert P. H., Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987 Sep 4;237(4819):1210–1212. doi: 10.1126/science.3306918. [DOI] [PubMed] [Google Scholar]
  24. Habeshaw J. A., Dalgleish A. G., Bountiff L., Newell A. L., Wilks D., Walker L. C., Manca F. AIDS pathogenesis: HIV envelope and its interaction with cell proteins. Immunol Today. 1990 Nov;11(11):418–425. doi: 10.1016/0167-5699(90)90162-3. [DOI] [PubMed] [Google Scholar]
  25. Harouse J. M., Bhat S., Spitalnik S. L., Laughlin M., Stefano K., Silberberg D. H., Gonzalez-Scarano F. Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide. Science. 1991 Jul 19;253(5017):320–323. doi: 10.1126/science.1857969. [DOI] [PubMed] [Google Scholar]
  26. Hofman F. M., von Hanwehr R. I., Dinarello C. A., Mizel S. B., Hinton D., Merrill J. E. Immunoregulatory molecules and IL 2 receptors identified in multiple sclerosis brain. J Immunol. 1986 May 1;136(9):3239–3245. [PubMed] [Google Scholar]
  27. Hwang S. S., Boyle T. J., Lyerly H. K., Cullen B. R. Identification of the envelope V3 loop as the primary determinant of cell tropism in HIV-1. Science. 1991 Jul 5;253(5015):71–74. doi: 10.1126/science.1905842. [DOI] [PubMed] [Google Scholar]
  28. Israël N., Hazan U., Alcami J., Munier A., Arenzana-Seisdedos F., Bachelerie F., Israël A., Virelizier J. L. Tumor necrosis factor stimulates transcription of HIV-1 in human T lymphocytes, independently and synergistically with mitogens. J Immunol. 1989 Dec 15;143(12):3956–3960. [PubMed] [Google Scholar]
  29. 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]
  30. 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]
  31. LaRosa G. J., Davide J. P., Weinhold K., Waterbury J. A., Profy A. T., Lewis J. A., Langlois A. J., Dreesman G. R., Boswell R. N., Shadduck P. Conserved sequence and structural elements in the HIV-1 principal neutralizing determinant. Science. 1990 Aug 24;249(4971):932–935. doi: 10.1126/science.2392685. [DOI] [PubMed] [Google Scholar]
  32. Levy J. A., Hoffman A. D., Kramer S. M., Landis J. A., Shimabukuro J. M., Oshiro L. S. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS. Science. 1984 Aug 24;225(4664):840–842. doi: 10.1126/science.6206563. [DOI] [PubMed] [Google Scholar]
  33. Lieberman A. P., Pitha P. M., Shin H. S., Shin M. L. Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6348–6352. doi: 10.1073/pnas.86.16.6348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lindholm D., Heumann R., Meyer M., Thoenen H. Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal cells of rat sciatic nerve. Nature. 1987 Dec 17;330(6149):658–659. doi: 10.1038/330658a0. [DOI] [PubMed] [Google Scholar]
  35. Maddon P. J., Dalgleish A. G., McDougal J. S., Clapham P. R., Weiss R. A., Axel R. The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain. Cell. 1986 Nov 7;47(3):333–348. doi: 10.1016/0092-8674(86)90590-8. [DOI] [PubMed] [Google Scholar]
  36. Martin S., Maruta K., Burkart V., Gillis S., Kolb H. IL-1 and IFN-gamma increase vascular permeability. Immunology. 1988 Jun;64(2):301–305. [PMC free article] [PubMed] [Google Scholar]
  37. Matsushita S., Robert-Guroff M., Rusche J., Koito A., Hattori T., Hoshino H., Javaherian K., Takatsuki K., Putney S. Characterization of a human immunodeficiency virus neutralizing monoclonal antibody and mapping of the neutralizing epitope. J Virol. 1988 Jun;62(6):2107–2114. doi: 10.1128/jvi.62.6.2107-2114.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Merrill J. E. Effects of interleukin-1 and tumor necrosis factor-alpha on astrocytes, microglia, oligodendrocytes, and glial precursors in vitro. Dev Neurosci. 1991;13(3):130–137. doi: 10.1159/000112150. [DOI] [PubMed] [Google Scholar]
  39. Merrill J. E., Koyanagi Y., Chen I. S. Interleukin-1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor. J Virol. 1989 Oct;63(10):4404–4408. doi: 10.1128/jvi.63.10.4404-4408.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Merrill J. E., Kutsunai S., Mohlstrom C., Hofman F., Groopman J., Golde D. W. Proliferation of astroglia and oligodendroglia in response to human T cell-derived factors. Science. 1984 Jun 29;224(4656):1428–1430. doi: 10.1126/science.6610212. [DOI] [PubMed] [Google Scholar]
  41. Merrill J. E., Strom S. R., Ellison G. W., Myers L. W. In vitro study of mediators of inflammation in multiple sclerosis. J Clin Immunol. 1989 Mar;9(2):84–96. doi: 10.1007/BF00916935. [DOI] [PubMed] [Google Scholar]
  42. Merrill J. E., Zimmerman R. P. Natural and induced cytotoxicity of oligodendrocytes by microglia is inhibitable by TGF beta. Glia. 1991;4(3):327–331. doi: 10.1002/glia.440040311. [DOI] [PubMed] [Google Scholar]
  43. Moore J. P., McKeating J. A., Weiss R. A., Sattentau Q. J. Dissociation of gp120 from HIV-1 virions induced by soluble CD4. Science. 1990 Nov 23;250(4984):1139–1142. doi: 10.1126/science.2251501. [DOI] [PubMed] [Google Scholar]
  44. O'Brien W. A., Koyanagi Y., Namazie A., Zhao J. Q., Diagne A., Idler K., Zack J. A., Chen I. S. HIV-1 tropism for mononuclear phagocytes can be determined by regions of gp120 outside the CD4-binding domain. Nature. 1990 Nov 1;348(6296):69–73. doi: 10.1038/348069a0. [DOI] [PubMed] [Google Scholar]
  45. Perry V. H., Gordon S. Modulation of CD4 antigen on macrophages and microglia in rat brain. J Exp Med. 1987 Oct 1;166(4):1138–1143. doi: 10.1084/jem.166.4.1138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Peudenier S., Hery C., Montagnier L., Tardieu M. Human microglial cells: characterization in cerebral tissue and in primary culture, and study of their susceptibility to HIV-1 infection. Ann Neurol. 1991 Feb;29(2):152–161. doi: 10.1002/ana.410290207. [DOI] [PubMed] [Google Scholar]
  47. Poli G., Bressler P., Kinter A., Duh E., Timmer W. C., Rabson A., Justement J. S., Stanley S., Fauci A. S. Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms. J Exp Med. 1990 Jul 1;172(1):151–158. doi: 10.1084/jem.172.1.151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Popovic M., Read-Connole E., Gallo R. C. T4 positive human neoplastic cell lines susceptible to and permissive for HTLV-III. Lancet. 1984 Dec 22;2(8417-8418):1472–1473. doi: 10.1016/s0140-6736(84)91666-0. [DOI] [PubMed] [Google Scholar]
  49. Ratner L., Haseltine W., Patarca R., Livak K. J., Starcich B., Josephs S. F., Doran E. R., Rafalski J. A., Whitehorn E. A., Baumeister K. Complete nucleotide sequence of the AIDS virus, HTLV-III. Nature. 1985 Jan 24;313(6000):277–284. doi: 10.1038/313277a0. [DOI] [PubMed] [Google Scholar]
  50. Rusche J. R., Lynn D. L., Robert-Guroff M., Langlois A. J., Lyerly H. K., Carson H., Krohn K., Ranki A., Gallo R. C., Bolognesi D. P. Humoral immune response to the entire human immunodeficiency virus envelope glycoprotein made in insect cells. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6924–6928. doi: 10.1073/pnas.84.19.6924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Salahuddin S. Z., Ablashi D. V., Hunter E. A., Gonda M. A., Sturzenegger S., Markham P. D., Gallo R. C. HTLV-III infection of EBV-genome-positive B-lymphoid cells with or without detectable T4 antigens. Int J Cancer. 1987 Feb 15;39(2):198–202. doi: 10.1002/ijc.2910390213. [DOI] [PubMed] [Google Scholar]
  52. Sanchez-Pescador R., Power M. D., Barr P. J., Steimer K. S., Stempien M. M., Brown-Shimer S. L., Gee W. W., Renard A., Randolph A., Levy J. A. Nucleotide sequence and expression of an AIDS-associated retrovirus (ARV-2). Science. 1985 Feb 1;227(4686):484–492. doi: 10.1126/science.2578227. [DOI] [PubMed] [Google Scholar]
  53. Sapolsky R., Rivier C., Yamamoto G., Plotsky P., Vale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science. 1987 Oct 23;238(4826):522–524. doi: 10.1126/science.2821621. [DOI] [PubMed] [Google Scholar]
  54. Shioda T., Levy J. A., Cheng-Mayer C. Macrophage and T cell-line tropisms of HIV-1 are determined by specific regions of the envelope gp120 gene. Nature. 1991 Jan 10;349(6305):167–169. doi: 10.1038/349167a0. [DOI] [PubMed] [Google Scholar]
  55. Skinner M. A., Ting R., Langlois A. J., Weinhold K. J., Lyerly H. K., Javaherian K., Matthews T. J. Characteristics of a neutralizing monoclonal antibody to the HIV envelope glycoprotein. AIDS Res Hum Retroviruses. 1988 Jun;4(3):187–197. doi: 10.1089/aid.1988.4.187. [DOI] [PubMed] [Google Scholar]
  56. Watkins B. A., Dorn H. H., Kelly W. B., Armstrong R. C., Potts B. J., Michaels F., Kufta C. V., Dubois-Dalcq M. Specific tropism of HIV-1 for microglial cells in primary human brain cultures. Science. 1990 Aug 3;249(4968):549–553. doi: 10.1126/science.2200125. [DOI] [PubMed] [Google Scholar]
  57. Webb D. S., Shimizu Y., Van Seventer G. A., Shaw S., Gerrard T. L. LFA-3, CD44, and CD45: physiologic triggers of human monocyte TNF and IL-1 release. Science. 1990 Sep 14;249(4974):1295–1297. doi: 10.1126/science.1697984. [DOI] [PubMed] [Google Scholar]
  58. Westervelt P., Gendelman H. E., Ratner L. Identification of a determinant within the human immunodeficiency virus 1 surface envelope glycoprotein critical for productive infection of primary monocytes. Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3097–3101. doi: 10.1073/pnas.88.8.3097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. 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]
  60. Zack J. A., Arrigo S. J., Weitsman S. R., Go A. S., Haislip A., Chen I. S. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990 Apr 20;61(2):213–222. doi: 10.1016/0092-8674(90)90802-l. [DOI] [PubMed] [Google Scholar]

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