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.
Similar content being viewed by others
References
Achim CL, Wang R, Miners DK, Wiley CA (1994). Brain viral burden in HIV infection. J Neuropathol Exp Neurol 53: 284–294.
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.
Armitage RJ, Maliszewski CR, Alderson MR, Grabstein KH, Spriggs MK, Fanslow WC (1993). CD40L: a multifunctional ligand. Semin Immunol 5: 401–412.
Banchereau J, Steinman RM (1998). Dendritic cells and the control of immunity. Nature 392: 245–252.
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.
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.
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.
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.
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.
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.
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.
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.
English R, Johnson C, Gebhard DH, Tompkins MB (1993). In vivo lymphocyte tropism of feline immunodeficiency virus. J Virol 67: 5175–5186.
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.
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.
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.
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.
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.
Giulian D, Vaca K, Noonan CA (1990). Secretion of neurotoxins by mononuclear phagocytes infected with HIV-1. Science 250: 1593–1596.
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.
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.
Gray F, Hurtrel M, Hurtrel B (1996). Early central nervous system changes in human immunodeficiency virus (HIV)-infection. Neuropathol Appl Neurobiol 19: 3–9.
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.
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.
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.
Kornbluth RS (2000). The emerging role of CD40 ligand in HIV infection. J Leukoc Biol 68: 373–382.
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.
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.
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.
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.
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.
Lipton S (1992). Requirement of macrophages in neuronal injury induced by HIV envelope protein gp120. NeuroReport 3: 913–915.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Meeker RB, Robertson K, Barry T, Hall C (1999b). Neurotoxicity of CSF from HIV-infected humans. J NeuroVirol 5: 507–518.
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.
Nath A, Geiger J (1998). Neurobiological aspects of human immunodeficiency virus infection: neurotoxic mechanisms. Prog Neurobiol 54: 19–33.
Navia BA, Cho ES, Petito CK, Price RW (1986). The AIDS dementia complex: II. Neuropathology. Ann Neurol 19: 525–535.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by National Institutes of Health Grant NS33408 and the UNC Center for AIDS Research 9P30 AI50410.
Rights and permissions
About this article
Cite this article
Bragg, D.C., Hudson, L.C., Liang, Y.H. et al. Choroid plexus macrophages proliferate and release toxic factors in response to feline immunodeficiency virus. Journal of NeuroVirology 8, 225–239 (2002). https://doi.org/10.1080/13550280290049679
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1080/13550280290049679