Journal of NeuroVirology

, Volume 8, Issue 3, pp 225–239 | Cite as

Choroid plexus macrophages proliferate and release toxic factors in response to feline immunodeficiency virus

  • D. C. Bragg
  • L. C. Hudson
  • Y. H. Liang
  • M. B. Tompkins
  • A. Fernandes
  • R. B. Meeker
Article

Abstract

Recent observations have suggested that lentiviruses stimulate the proliferation and activation of microglia. A similar effect within the dense macrophage population of the choroid plexus could have significant implications for trafficking of virus and inflammatory cells into the brain. To explore this possibility, we cultured fetal feline macrophages and examined their response to feline immunodeficiency virus (FIV) or the T-cell-derived protein, recombinant human CD40-ligand trimer (rhuCD40-L). The rhCD40-L was the most potent stimulus for macrophage proliferation, often inducing a dramatic increase in macrophage density. Exposure to FIV resulted in a small increase in the number of macrophages and macrophage nuclei labeled with bromodeoxyuridine. The increase in macrophage density after FIV infection also correlated with an increase in neurotoxic activity of the macrophage-conditione d medium. Starting at 16–18 weeks postinfection, well after the peak of viremia, a similar toxic activity was detected in cerebrospinal fluid (CSF) from FIV-infected cats. Toxicity in the CSF increased over time and was paralleled by strong CD18 staining of macrophages/microglia in the choroid plexus and adjacent parenchyma. These results suggest that lentiviral infection of the choroid plexus can induce a toxic inflammatory response that is fueled by local macrophage proliferation. Together with the observation of increasing toxic activity in the CSF and increased CD18 staining in vivo, these observations suggest that choroid plexus macrophages may contribute to an inflammatory cascade in the brain that progresses independently of systemic and CSF viral load.

Keywords

human immunodeficiency virus brain AIDS neural culture neurotoxicity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Achim CL, Wang R, Miners DK, Wiley CA (1994). Brain viral burden in HIV infection. J Neuropathol Exp Neurol 53: 284–294.PubMedCrossRefGoogle Scholar
  2. Adamson DC, Wildemann B, Sasaki M, Glass JD, MacArthur JC, Christov VI, Dawson TM, Dawson VL (1996). Immunologic NO synthetase: elevation in severe AIDS dementia and induction by HIV-1 gp41. Science 274: 1917–1921.PubMedCrossRefGoogle Scholar
  3. Armitage RJ, Maliszewski CR, Alderson MR, Grabstein KH, Spriggs MK, Fanslow WC (1993). CD40L: a multifunctional ligand. Semin Immunol 5: 401–412.PubMedCrossRefGoogle Scholar
  4. Banchereau J, Steinman RM (1998). Dendritic cells and the control of immunity. Nature 392: 245–252.PubMedCrossRefGoogle Scholar
  5. Beebe AM, Dua N, Faith TG, Moore PF, Pedersen NC, Dandekar S (1994). Primary stage of feline immunodeficiency virus infection: viral dissemination and cellular targets. J Virol 68: 3080–3091.PubMedCentralPubMedGoogle Scholar
  6. Bragg DC, Meeker RB, Duff BA, English RV, Tompkins MB (1999). Neurotoxicity of FIV and FIV envelope protein in feline cortical cultures. Brain Res 816: 431–437.PubMedCrossRefGoogle Scholar
  7. Bragg DC, Robertson K, Hall CD, Meeker RB (2000). Techniques to measure neurologic disease progression in HIV-1 patients. Science Online: NeuroAIDS 3: 1–9.Google Scholar
  8. Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C, Durand I, Banchereau J (1994). Activation of human dendritic cells through CD40 cross-linking. J Exp Med 180: 1263–1272.PubMedCrossRefGoogle Scholar
  9. Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, Gallo RC, Major EO (1998). Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci USA 95: 3117–3121.PubMedCrossRefGoogle Scholar
  10. Czub S, Muller JG, Czub M, Muller-Hermelink HK (1996). Nature and sequence of simian immunodeficiency virus-induced central nervous system lesions: a kinetic study. Acta Neuropathol (Berl) 92: 487–498.CrossRefGoogle Scholar
  11. Dean AF, Montgomery M, Baskerville A, Cook RW, Cranage MP, Sharpe SA, Dennis MJ, Luthert PJ, Hou S-T, Lantos PL (1993). Different patterns of neuropathological disease in rhesus monkeys infected by simian immunodeficiency virus, and their relation to the humoral immune response. Neuropathol Appl Neurobiol 19: 336–345.PubMedCrossRefGoogle Scholar
  12. Dow SW, Dreitz MJ, Hoover EA (1992). Feline immunodeficiency virus neurotropism: evidence that astrocytes and microglia are the primary target cells. Vet Immunol Immunopathol 35: 23–35.PubMedCrossRefGoogle Scholar
  13. English R, Johnson C, Gebhard DH, Tompkins MB (1993). In vivo lymphocyte tropism of feline immunodeficiency virus. J Virol 67: 5175–5186.PubMedCentralPubMedGoogle Scholar
  14. Everall IP, Luthert PJ, Lantos PL (1993). Neuronal number and volume alterations in the neocortex of HIV infected individuals. J Neurol Neurosurg Psych 56: 481–486.CrossRefGoogle Scholar
  15. Falangola MF, Hanly A, Galvao-Castro B, Petito CK (1995). HIV infection of human choroid plexus: a possible mechanism of viral entry into the CNS. J Neuropathol Exp Sci 54: 497–503.CrossRefGoogle Scholar
  16. Gabuzda DH, Ho DD, de la Monde SM, Hirsh MS, Rota TR, Sobel RA (1986). Immunohistochemical identification of HTLV-III antigen in brains of patients with AIDS. Ann Neurol 20: 289–295.PubMedCrossRefGoogle Scholar
  17. Gelbard HA, Nottet HS, Swindells S, Jett M, Dzenko KA, Genis P, White R, Wang L, Choi Y-B, Zhang D, Lipton SA, Tourtellotte WW, Epstein LG, Gendelman HE (1994). Platelet-activating factor: a candidate human immunodeficiency virus type 1-induced neurotoxin. J Virol 68: 4628–4635.PubMedCentralPubMedGoogle Scholar
  18. Gisslen M, Fuchs D, Svennerholm B, Hagberg L (1999). Cerebrospinal fluid viral load, intrathecal immunoactivation, and cerebrospinal fluid monocytic cell count in HIV-1 infection. J Acquir Immune Defic Syndr 21: 271–276.PubMedCrossRefGoogle Scholar
  19. Giulian D, Vaca K, Noonan CA (1990). Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 250: 1593–1596.PubMedCrossRefGoogle Scholar
  20. Giulian D, Yu J, Li X, Tom D, Li J, Wendt E, Lin S-N, Schwarcz R, Noonan C (1996). Study of receptor-mediated neurotoxins released by HIV-1-infected mononuclear phagocyte s found in human brain. J Neurosci 16: 3139–3153.PubMedGoogle Scholar
  21. Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995). Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 38: 755–762.PubMedCrossRefGoogle Scholar
  22. Gray F, Hurtrel M, Hurtrel B (1996). Early central nervous system changes in human immunodeficiency virus (HIV)-infection. Neuropathol Appl Neurobiol 19: 3–9.CrossRefGoogle Scholar
  23. Hanly A, Petito CK (1998). HLA-DR-positive dendritic cells of the normal human choroid plexus. A potential reservoir of HIV in the central nervous system. Human Pathol 29: 88–93.CrossRefGoogle Scholar
  24. Heyes MP, Saito K, Lackner A, Wiley CA, Achim CL, Markey SP (1998). Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. FASEB J 12: 881–896.PubMedGoogle Scholar
  25. Koenig S, Gendelman HE, Orenstein JM, Dal Canto MC, Pezeshkpour GH, Yungbluth M, Janotta F, Aksamit A, Martin MA, Fauci AS (1986). Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233: 1089–1093.PubMedCrossRefGoogle Scholar
  26. Kornbluth RS (2000). The emerging role of CD40 ligand in HIV infection. J Leukoc Biol 68: 373–382.PubMedGoogle Scholar
  27. Lackner AA, Smith MO, Munn RJ, Martfeld DJ, Gardner MB, Marx PA, Dandekar S (1991). Localization of simian immunodeficiency virus in the central nervous system of rhesus monkeys. Am J Pathol 139: 609–621.PubMedGoogle Scholar
  28. Lafrenie RM, Wahl LM, Epstein JS, Hewlett IK, Yamada KM, Dhawan S (1996). HIV-1-Tat protein promotes chemotaxis and invasive behavior by monocytes. J Immunol 157: 974–977.PubMedGoogle Scholar
  29. Lane JH, Tarantal AF, Pauley D, Marthas M, Miller CJ, Lackner AA (1996). Localization of simian immunodeficiency virus nucleic acid and antigen in brains of fetal macaques inoculated in utero. Am J Pathol 149: 1097–1104.PubMedGoogle Scholar
  30. Ling EA (1979). Ultrastruct and origin of epiplexus cells in the telencephalic choroid plexus of postnatal rats studied by intravenous injection of carbon particles. J Anat 129: 479–492.PubMedGoogle Scholar
  31. Ling EA, Kaur C, Lu J (1998). Origin, nature, and some functional considerations of intraventricular macrophages, with special reference to the epiplexus cells. Microsc Res Tech 41: 43–56.PubMedCrossRefGoogle Scholar
  32. Lipton S (1992). Requirement of macrophages in neuronal injury induced by HIV envelope protein gp120. NeuroReport 3: 913–915.PubMedCrossRefGoogle Scholar
  33. Lu J, Kaur C, Ling EA (1993). Intraventricular macrophages in the lateral ventricles with special reference to epiplexus cells: a quantitative analysis and their uptake of fluorescent tracer injected intraperitoneally in rats of different ages. J Anat 183(Pt 2): 405–414.PubMedGoogle Scholar
  34. Magnuson D, Knudsen B, Geiger J, Brownstone R, Nath A (1995). Human immunodeficiecy virus type 1 Tat activates non-N-methyl-d-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann Neurol 37: 373–380.PubMedCrossRefGoogle Scholar
  35. Martin C, Albert J, Hansson P, Pehrsson P, Link H, Sonnerborg A (1998). Cerebrospinal fluid mononuclear cell counts influence CSF HIV-1 RNA levels. J Acquir Immune Defic Syndr Hum Retrovirol 17: 214–219.PubMedCrossRefGoogle Scholar
  36. Matyszak MK, Lawson LJ, Perry VH, Gordon S (1992). Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class 2 antigens. J Neuroimmunol 40: 173–182.PubMedCrossRefGoogle Scholar
  37. Matyszak MK, Perry V (1996). The potential role of dendritic cells in immune-mediated inflammatory diseases of the central nervous system. Neuroscience 74: 599–608.PubMedCrossRefGoogle Scholar
  38. McArthur JC, Sipos E, Cornblath DR, Welch D, Chupp M, Griffin DE, Johnson RT (1989). Identification of mononuclear cells in CSF of patients with HIV infection. Neurology 39: 66–70.PubMedCrossRefGoogle Scholar
  39. McMenamin PG (1999). Distribution and phenotype of dendritic cells and resident tissue macrophages in the dura mater, leptomeninges, and choroid plexus of the rat brain as demonstrated in wholemount preparations. J Comp Neurol 405: 553–562.PubMedCrossRefGoogle Scholar
  40. Meeker RB, Azuma Y, Bragg DC, English RV, Tompkins M (1999a). Microglial proliferation in cortical neural cultures exposed to feline immunodeficiency virus. J Neuroimmunol 101: 15–26.PubMedCrossRefGoogle Scholar
  41. Meeker RB, English R, Tompkins M (1996). Enhanced excitotoxicity in primary feline neural cultures exposed to feline immunodeficiency virus (FIV). J NeuroAIDS 1: 1–27.Google Scholar
  42. Meeker RB, Robertson K, Barry T, Hall C (1999b). Neurotoxicity of CSF from HIV-infected humans. J NeuroVirol 5: 507–518.PubMedCrossRefGoogle Scholar
  43. Meeker RB, Thiede BA, Hall C, English R, Tompkins M (1997). Cortical cell loss in asymptomatic cats experimentally infected with feline immunodeficiency virus. AIDS Res Hum Retroviruses 13: 1131–1140.PubMedCrossRefGoogle Scholar
  44. Nath A, Geiger J (1998). Neurobiological aspects of human immunodeficiency virus infection: neurotoxic mechanisms. Prog Neurobiol 54: 19–33.PubMedCrossRefGoogle Scholar
  45. Navia BA, Cho ES, Petito CK, Price RW (1986). The AIDS dementia complex: II. Neuropathology. Ann Neurol 19: 525–535.PubMedCrossRefGoogle Scholar
  46. Nottet HSLM, Persidsky Y, Sasseville VG, Nukuna AN, Bock P, Zhai Q, Sharer LR, McComb RD, Swindells S, Soderland C, Gendelman HE (1996). Mechanisms for the transendothelial migration of HIV-1-infected monocytes into brain. J Immunol 156: 1284–1295.PubMedGoogle Scholar
  47. Persidsky Y, Stins M, Way D, Witte MH, Weinand M, Kim KS, Bock P, Gendelman HE, Fiala M (1997). A model for monocyte migration through the blood—brain barrier during HIV-1 encephalitis. J Immunol 158: 3499–3510.PubMedGoogle Scholar
  48. Petito CK, Chen H, Mastri AR, Torres-Munoz J, Roberts B, Wood C (1999). HIV infection of choroid plexus in AIDS and asymptomatic HIV-infected patients suggests that the choroid plexus may be a reservoir of productive infection. J NeuroVirol 5: 670–677.PubMedCrossRefGoogle Scholar
  49. Podell M, Maruyama K, Smith M, Hayes KA, Buck WR, Ruehlmann DS, Mathes LE (1999). Frontal lobe neuronal injury correlates to altered function in FIV-infected cats. J Acquir Immune Defic Syndr 22: 10–18.PubMedCrossRefGoogle Scholar
  50. Poli A, Pistello M, Carli MA, Abramo F, Mancuso G, Nicoletti E, Bendinelli M (1999). Tumor necrosis factor-alpha and virus expression in the central nervous system of cats infected with feline immunodeficiency virus. J Neuro Virol 5: 465–473.Google Scholar
  51. Pulliam L, Herndier BG, Tang NM, McGrath MS (1991). Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains. J Clin Invest 87: 503–512.PubMedCentralPubMedCrossRefGoogle Scholar
  52. Rausch DM, Heyes MP, Murray EA, Lendvay J, Sharer LR, Ward JM, Rehm S, Nohr D, Weihe E, Eiden LE (1994). Cytopathologic and neurochemical correlates of progression to motor/cognitive impairment in SIV-infected rhesus monkeys. J Neuropathol Exp Neurol 53: 165–175.PubMedCrossRefGoogle Scholar
  53. Rottman JB, Tompkins WA, Tompkins MB (1996). A reverse transcription-quantitative competitive polymerase chain reaction (RT-qcPCR) technique to measure cytokine gene expression in domestic mammals. Vet Pathol 33: 242–248.PubMedCrossRefGoogle Scholar
  54. Serot JM, Foliguet B, Bene MC, Faure GC (1997). Ultrastructural and immunohistological evidence for dendritic-like cells within human choroid plexus epithelium. NeuroReport 8: 1995–1998.PubMedCrossRefGoogle Scholar
  55. Sopper S, Demuth M, Stahl-Hennig C, Hunsmann G, Plesker R, Coulibaly C, Czub S, Ceska M, Koutsilieri E, Riederer P, Brinkmann R, Katz M, ter Meulen V (1996). The effect of simian immunodeficiency virus infection in vitro and in vivo on the cytokine production of isolated microglia and peripheral macrophages from rhesus monkey. Virology 220: 320–329.PubMedCrossRefGoogle Scholar
  56. Steffen BJ, Breier G, Butcher EC, Schulz M, Engelhardt B (1996) ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. Am J Pathol 148: 1819–1838.PubMedGoogle Scholar
  57. Steigerwald ES, Sarter M, March P, Podell M (1999). Effects of feline immunodeficiency virus on cognition and behavioral function in cats. J Acquir Immune Defic Syndr Hum Retrovirol 20: 411–419.PubMedCrossRefGoogle Scholar
  58. Takahashi K, Wesselingh SL, Griffin DE, McArthur JC, Johnson RT, Glass JD (1996). Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunohistochemistry. Ann Neurol 39: 705–711.PubMedCrossRefGoogle Scholar
  59. Weiss JM, Nath A, Major EO, Berman JW (1999). HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood—brain barrier and up-regulates CCR5 expression on human monocytes. J Immunol 163: 2953–2959.PubMedGoogle Scholar
  60. Wesselingh SL, Takahashi K, Glass JD, McArthur JC, Griffin JW, Griffin DE (1997). Cellular localization of tumor necrosis factor mRNA in neurological tissue from HIV-infected patients by combined reverse transcriptase/polymerase chain reaction in situ hybridization and immunohistochemistry. J Neuroimmunol 74: 1–8.PubMedCrossRefGoogle Scholar
  61. Wiley C, Masliah E, Morey M, Lemere C, DeTeresa R, Grafe M, Hansen L, Terry R (1991). Neocortical damage during HIV infection. Ann Neurol 29: 651–657.PubMedCrossRefGoogle Scholar
  62. Wolburg K, Gerhardt H, Schulz M, Wolburg H, Engelhardt B (1999). Ultrastructural localization of adhesion molecules in the healthy and inflamed choroid plexus of the mouse. Cell Tissue Res 296: 259–269.PubMedCrossRefGoogle Scholar
  63. Xiong H, Zeng YC, Lewis T, Zheng J, Persidsky Y, Gendelman HE (2000). HIV-1 infected mononuclear phagocyte secretory products affect neuronal physiology leading to cellular demise: relevance for HIV-1-associated dementia. J Neuro Virol 6(Suppl 1): S14-S23.Google Scholar
  64. Yang J-S, English RV, Ritchey JW, Davidson MG, Wasmoen T, Levy JK, Gebhard DH, Tompkins MB, Tompkins WAF (1996). Molecularly cloned feline immunodeficiency virus NCSU1 JSY3 induces immunodeficiency in specific-pathogen-free cats. J Virol 70: 3011–3017.PubMedCentralPubMedGoogle Scholar
  65. Yeung MC, Pulliam L, Lau AS (1995). The HIV envelope protein gp120 is toxic to human brain-cell cultures through the induction of interleukin-6 and tumor necrosis factor-alpha. AIDS 9: 137–143.PubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2002

Authors and Affiliations

  • D. C. Bragg
    • 1
    • 4
  • L. C. Hudson
    • 2
  • Y. H. Liang
    • 3
  • M. B. Tompkins
    • 3
  • A. Fernandes
    • 1
  • R. B. Meeker
    • 1
    • 2
  1. 1.Neurobiology Curriculum and Department of NeurologyUniversity of North CarolinaChapel Hill
  2. 2.Department of Anatomy, Physiological Sciences and Radiology, College of Veterinary MedicineNorth Carolina State UniversityRaleigh
  3. 3.Department of Microbiology, Parasitology and Pathology, College of Veterinary MedicineNorth Carolina State UniversityRaleigh
  4. 4.Molecular Neurogenetics UnitMassachusetts General HospitalCharlestown

Personalised recommendations