Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease

Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, > 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to- cell interactions between HIV-infected brain macrophages and astrocytes.

[1]  R. Huebner,et al.  Propagation of human tumors in antithymocyte serum-treated mice. , 1974, Journal of the National Cancer Institute.

[2]  P. Lantos,et al.  Neuronal loss in the frontal cortex in HIV infection , 1991, The Lancet.

[3]  J. Satoh,et al.  Cytokine‐lnduced Expression of Intercellular Adhesion Molecule‐1 (ICAM‐1) in Cultured Human Oligodendrocytes and Astrocytes , 1991, Journal of neuropathology and experimental neurology.

[4]  D. Bigner,et al.  Heterogeneity of Genotypic and Phenotypic Characteristics of Fifteen Permanent Cell Lines Derived from Human Gliomas , 1981, Journal of neuropathology and experimental neurology.

[5]  H. Gendelman,et al.  The macrophage in the persistence and pathogenesis of HIV infection. , 1989, AIDS.

[6]  E. Vivés,et al.  Evidence for neurotoxic activity of tat from human immunodeficiency virus type 1. , 1991, Journal of virology.

[7]  Karen L. Elkins,et al.  Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide , 1988, Nature.

[8]  J. Mills,et al.  ISOLATION OF AIDS-ASSOCIATED RETROVIRUSES FROM CEREBROSPINAL FLUID AND BRAIN OF PATIENTS WITH NEUROLOGICAL SYMPTOMS , 1985, The Lancet.

[9]  D. Volsky,et al.  Efficient binding, fusion and entry of HIV1 into CD4- negative neural cells : a mechanism for neuropathogenesis in AIDS , 1991 .

[10]  H. Gendelman,et al.  A selective defect of interferon alpha production in human immunodeficiency virus-infected monocytes , 1991, The Journal of experimental medicine.

[11]  C. Cheng‐Mayer,et al.  Human immunodeficiency virus can productively infect cultured human glial cells. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[12]  A. Harel-Bellan,et al.  Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[13]  J. Gold,et al.  ACUTE AIDS RETROVIRUS INFECTION Definition of a Clinical Illness Associated with Seroconversion , 1985, The Lancet.

[14]  G. Shaw,et al.  HTLV-III infection in brains of children and adults with AIDS encephalopathy. , 1985, Science.

[15]  D. Belin,et al.  Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors , 1986, The Journal of experimental medicine.

[16]  L. Montagnier,et al.  Human immunodeficiency virus type 1–infected monocytic cells can destroy human neural cells after cell‐to‐cell adhesion , 1992, Annals of neurology.

[17]  M. Stoler,et al.  Human T-cell lymphotropic virus type III infection of the central nervous system. A preliminary in situ analysis. , 1986, JAMA.

[18]  J. Orenstein,et al.  Macrophage- and astrocyte-derived transforming growth factor beta as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome , 1991, The Journal of experimental medicine.

[19]  J. Hoxie,et al.  CD4-independent infection of human neural cells by human immunodeficiency virus type 1 , 1989, Journal of Virology.

[20]  R. Schwarcz,et al.  Localization of quinolinic acid metabolizing enzymes in the rat brain. immunohistochemical studies using antibodies to 3-hydroxyanthranilic acid oxygenase and quinolinic acid phosphoribosyltransferase , 1988, Neuroscience.

[21]  A. Fauci,et al.  The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. , 1988, Science.

[22]  M. McGrath,et al.  Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. , 1991, The Journal of clinical investigation.

[23]  D. Griffin,et al.  Neopterin and interferon‐gamma in serum and cerebrospinal fluid of patients with HIV‐associated neurologic disease , 1991, Neurology.

[24]  R. Schooley,et al.  Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. , 1985, The New England journal of medicine.

[25]  A. Kriegstein,et al.  Glutamate neurotoxicity in cortical cell culture , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[26]  H. Gendelman,et al.  No direct neuronotoxicity by HIV-1 virions or culture fluids from HIV-1-infected T cells or monocytes. , 1992, AIDS research and human retroviruses.

[27]  C. Brosnan,et al.  Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor. , 1990, Journal of immunology.

[28]  S. Zuckerman,et al.  Transcriptional and post-transcriptional mechanisms involved in the differential expression of LPS-induced IL-1 and TNF mRNA. , 1991, Immunology.

[29]  M. Shin,et al.  Production of cytotoxic factor for oligodendrocytes by stimulated astrocytes. , 1987, Journal of immunology.

[30]  D. Giulian,et al.  Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1 , 1990, Science.

[31]  D. Ho,et al.  Intra-blood-brain-barrier synthesis of HTLV-III-specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex. , 1985, The New England journal of medicine.

[32]  J. Sidtis,et al.  Quinolinic acid in cerebrospinal fluid and serum in HIV‐1 Infection: Relationship to clinical and neurological status , 1991, Annals of neurology.

[33]  M. Reale,et al.  The combination of interleukin 1 plus tumor necrosis factor causes greater generation of LTB4, thromboxanes and aggregation on human macrophages than these compounds alone. , 1989, Progress in clinical and biological research.

[34]  R. Price,et al.  The AIDS dementia complex. , 1988, The Journal of infectious diseases.

[35]  J. Pontén,et al.  Determinants for the establishment of permanent tissue culture lines from human gliomas. , 2009, Acta pathologica et microbiologica Scandinavica. Section A, Pathology.

[36]  C. Wiley,et al.  Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[37]  O. Selnes,et al.  Cerebrospinal fluid abnormalities in homosexual men with and without neuropsychiatric findings , 1988, Annals of neurology.

[38]  E. Benveniste,et al.  Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. , 1990, Journal of immunology.

[39]  S. Dewhurst,et al.  Susceptibility of human glial cells to infection with human immunodeficiency virus (HIV) , 1987, FEBS letters.

[40]  S. Skaper,et al.  An automated colorimetric microassay for neuronotrophic factors. , 1986, Brain research.

[41]  M. Vasko,et al.  Prostaglandin E2 increases calcium conductance and stimulates release of substance P in avian sensory neurons , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  K. Selmaj,et al.  Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro , 1988, Annals of neurology.

[43]  K. McCarthy,et al.  Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue , 1980, The Journal of cell biology.

[44]  A. Fauci,et al.  Astrocyte-conditioned medium stimulates HIV-1 expression in a chronically infected promonocyte clone , 1990, Journal of Neuroimmunology.

[45]  D. Gingras,et al.  Platelet-activating factor (PAF-acether) enhances the concomitant production of tumour necrosis factor-alpha and interleukin-1 by subsets of human monocytes. , 1991, Immunology.

[46]  D. Burke,et al.  Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes , 1988, The Journal of experimental medicine.

[47]  B. Navia,et al.  The AIDS dementia complex: II. Neuropathology , 1986, Annals of neurology.

[48]  H. Gendelman,et al.  Neurological Aspects of Human Immunodeficiency Virus Infection , 1992 .

[49]  Michael S. B. Edwards,et al.  A Trojan Horse mechanism for the spread of visna virus in monocytes. , 1985, Virology.

[50]  H. Mayan,et al.  [AIDS dementia]. , 2020, Harefuah.

[51]  C. Brosnan,et al.  Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. , 1991, The Journal of clinical investigation.

[52]  C. Dubois,et al.  Platelet-activating factor (PAF) enhances tumor necrosis factor production by alveolar macrophages. Prevention by PAF receptor antagonists and lipoxygenase inhibitors. , 1989, Journal of immunology.

[53]  J. Glass,et al.  Cytokine expression in the brain during the acquired immunodeficiency syndrome , 1992, Annals of neurology.

[54]  T. Hökfelt,et al.  Leukotrienes in the rat central nervous system. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. Lipton,et al.  HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. , 1990, Science.

[56]  L. Epstein,et al.  Human immunodeficiency virus type 1 (HIV-1) infection of the nervous system: a review. , 1988, Immunodeficiency reviews.

[57]  H. Gendelman,et al.  Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. , 1986, Science.

[58]  S. Pestka,et al.  Convenient assay for interferons , 1981, Journal of virology.

[59]  N. Brousse,et al.  AIDS subacute encephalitis. Identification of HIV-infected cells. , 1987, The American journal of pathology.

[60]  H. Pollard,et al.  PC12 cells differentiate into chromaffin cell-like phenotype in coculture with adrenal medullary endothelial cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[61]  J. Sidtis,et al.  The aids dementia complex: Some current questions , 1988, Annals of neurology.

[62]  E. Masliah,et al.  Neocortical damage during HIV infection , 1991, Annals of neurology.

[63]  J. Merrill,et al.  Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human immunodeficiency virus type 1 , 1992, Journal of virology.

[64]  E. Wolters,et al.  Intrathecal synthesis of antibodies to HTLV-III in patients without AIDS or AIDS related complex. , 1986, British medical journal.

[65]  J. Barrett,et al.  Serum factor supporting long-term survival of rat central neurons in culture. , 1983, Science.

[66]  M. Hirsch,et al.  Immunohistochemical identification of HTLV‐III antigen in brains of patients with AIDS , 1986, Annals of neurology.

[67]  M. Lairmore,et al.  Spontaneous interferon production by pulmonary leukocytes is associated with lentivirus-induced lymphoid interstitial pneumonia. , 1988, Journal of immunology.

[68]  S. Gordon,et al.  Biology of the Macrophage , 1986, Journal of Cell Science.

[69]  Y. Seyama,et al.  Enzymic Synthesis of Leukotriene B4 in Guinea Pig Brain , 1987, Journal of neurochemistry.

[70]  M. Shin,et al.  Production of tumor necrosis factor and other cytokines by astrocytes stimulated with lipopolysaccharide or a neurotropic virus. , 1989, Proceedings of the National Academy of Sciences of the United States of America.