Cell and Tissue Research

, Volume 347, Issue 2, pp 443–455 | Cite as

Transmigration of macrophages across the choroid plexus epithelium in response to the feline immunodeficiency virus

  • Rick B. Meeker
  • D. C. Bragg
  • Winona Poulton
  • Lola Hudson
Regular Article


Although lentiviruses such as human, feline and simian immunodeficiency viruses (HIV, FIV, SIV) rapidly gain access to cerebrospinal fluid (CSF), the mechanisms that control this entry are not well understood. One possibility is that the virus may be carried into the brain by immune cells that traffic across the blood–CSF barrier in the choroid plexus. Since few studies have directly examined macrophage trafficking across the blood–CSF barrier, we established transwell and explant cultures of feline choroid plexus epithelium and measured trafficking in the presence or absence of FIV. Macrophages in co-culture with the epithelium showed significant proliferation and robust trafficking that was dependent on the presence of epithelium. Macrophage migration to the apical surface of the epithelium was particularly robust in the choroid plexus explants where 3-fold increases were seen over the first 24 h. Addition of FIV to the cultures greatly increased the number of surface macrophages without influencing replication. The epithelium in the transwell cultures was also permissive to PBMC trafficking, which increased from 17 to 26% of total cells after exposure to FIV. Thus, the choroid plexus epithelium supports trafficking of both macrophages and PBMCs. FIV significantly enhanced translocation of macrophages and T cells indicating that the choroid plexus epithelium is likely to be an active site of immune cell trafficking in response to infection.


HIV FIV Monocytes T cells Cerebrospinal fluid Brain Blood–brain barrier Trafficking 



This work was supported by NIH Grant MH 063646.


  1. Bossi P, Dupin N, Coutellier A, Bricaire F, Lubetzki C, Katlama C, Calvez V (1998) The level of human immunodeficiency virus (HIV) type 1 RNA in cerebrospinal fluid as a marker of HIV encephalitis. Clin Infect Dis 26:1072–1073PubMedCrossRefGoogle Scholar
  2. Boulton M, Flessner M, Armstrong D, Mohamed R, Hay J, Johnston M (1999) Contribution of extracranial lymphatics and arachnoid villi to the clearance of a CSF tracer in the rat. Am J Physiol 276:R818–R823PubMedGoogle Scholar
  3. Bragg D, Childers T, Tompkins M, Tompkins W, Meeker R (2002a) Infection of the choroid plexus by feline immunodeficiency virus. J Neurovirol 8:211–224PubMedCrossRefGoogle Scholar
  4. Bragg D, Hudson L, Liang Y, Tompkins M, Fernandes A, Meeker R (2002b) Choroid plexus macrophages proliferate and release toxic factors in response to feline immunodeficiency virus. J Neurovirol 8:225–239PubMedCrossRefGoogle Scholar
  5. Burkala EJ, He J, West JT, Wood C, Petito CK (2005) Compartmentalization of HIV-1 in the central nervous system: role of the choroid plexus. AIDS 19:675–684PubMedCrossRefGoogle Scholar
  6. Chang J, Jozwiak R, Wang B, Ng T, Ge YC, Bolton W, Dwyer DE, Randle C, Osborn R, Cunningham AL, Saksena NK (1998) Unique HIV type 1 V3 region sequences derived from six different regions of brain: region-specific evolution within host-determined quasispecies. AIDS Res Hum Retroviruses 14:25–30PubMedCrossRefGoogle Scholar
  7. Chen H, Wood C, Petito CK (2000) Comparisons of HIV-1 viral sequences in brain, choroid plexus and spleen: Potential role of choroid plexus in the pathogenesis of HIV encephalitis. J Neurovirol 6:498–506PubMedCrossRefGoogle Scholar
  8. Cinque P, Vago L, Ceresa D, Mainini F, Terreni MR, Vagani A, Torri W, Bossolasco S, Lazzarin A (1998) Cerebrospinal fluid HIV-1 RNA levels: correlation with HIV encephalitis. AIDS 12:389–394PubMedCrossRefGoogle Scholar
  9. Czub S, Muller JG, Czub M, Muller-Hermelink HK (1996) Impact of various simian immunodeficiency virus variants on induction and nature of neuropathology in macaques. Res Virol 147:165–170PubMedCrossRefGoogle Scholar
  10. Eggers CC, van Lunzen J, Buhk T, Stellbrink HJ (1999) HIV infection of the central nervous system is characterized by rapid turnover of viral RNA in cerebrospinal fluid. J Acquir Immune Defic Syndr Hum Retrovirol 20:259–264PubMedCrossRefGoogle Scholar
  11. Ellis RJ, Hsia K, Spector SA, Nelson JA, Heaton RK, Wallace MR, Abramson I, Atkinson JH, Grant I, McCutchan JA (1997) Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. HIV Neurobehavioral Research Center Group. Ann Neurol 42:679–688PubMedCrossRefGoogle Scholar
  12. Ellis RJ, Gamst AC, Capparelli E, Spector SA, Hsia K, Wolfson T, Abramson I, Grant I, McCutchan JA (2000) Cerebrospinal fluid HIV RNA originates from both local CNS and systemic sources. Neurology 54:927–936PubMedGoogle Scholar
  13. Elovaara I, Muller KM (1993) Cytoimmunological abnormalities in cerebrospinal fluid in early stages of HIV-1 infection often precede changes in blood. J Neuroimmunol 44:199–204PubMedCrossRefGoogle Scholar
  14. Epstein LG, Kuiken C, Blumberg BM, Hartman S, Sharer LR, Clement M, Goudsmit J (1991) HIV-1 V3 domain variation in brain and spleen of children with AIDS: tissuespecific evolution within host-determined quasispecies. Virology 180:583–590PubMedCrossRefGoogle 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 54:497–503CrossRefGoogle Scholar
  16. Fletcher NF, Bexiga MG, Brayden DJ, Brankin B, Willett BJ, Hosie MJ, Jacque JM, Callanan JJ (2009) Lymphocyte migration through the blood-brain barrier (BBB) in feline immunodeficiency virus infection is significantly influenced by the pre-existence of virus and tumour necrosis factor (TNF)-alpha within the central nervous system (CNS): studies using an in vitro feline BBB model. Neuropathol Appl Neurobiol 35:592–602PubMedCrossRefGoogle Scholar
  17. Gordon LB, Knopf PM, Cserr HF (1992) Ovalbumin is more immunogenic when introduced into brain or cerebrospinal fluid than into extracerebral sites. J Neuroimmunol 40:81–87PubMedCrossRefGoogle Scholar
  18. Haas DW, Johnson BW, Spearman P, Raffanti S, Nicotera J, Schmidt D, Hulgan T, Shepard R, Fiscus SA (2003) Two phases of HIV RNA decay in CSF during initial days of multidrug therapy. Neurology 61:1391–1396PubMedGoogle Scholar
  19. Hakvoort A, Haselbach M, Wegener J, Hoheisel D, Galla H-J (1998) The polarity of choroid plexus epithelial cells in vitro is improved in serum-free medium. J Neurochem 71:1141–1150PubMedCrossRefGoogle Scholar
  20. 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. Hum Pathol 29:88–93PubMedCrossRefGoogle Scholar
  21. Hudson LC, Bragg DC, Tompkins MB, Meeker RB (2005) Astrocytes and microglia differentially regulate trafficking of lymphocyte subsets across brain endothelial cells. Brain Res 1058:148–160PubMedCrossRefGoogle Scholar
  22. Kolb SA, Sporer B, Lahrtz F, Koedel U, Pfister HW, Fontana A (1999) Identification of a T cell chemotactic factor in the cerebrospinal fluid of HIV-1-infected individuals as interferon-gamma inducible protein 10. J Neuroimmunol 93:172–181PubMedCrossRefGoogle Scholar
  23. 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 139:609–621PubMedGoogle Scholar
  24. Lane JH, Sasseville VG, Smith MO, Vogel P, Pauley DR, Heyes MP, Lackner AA (1996) Neuroinvasion by simian immunodeficiency virus coincides with increased numbers of perivascular macrophages/microglia and intrathecal immune activation. J Neurovirol 2:423–432PubMedCrossRefGoogle Scholar
  25. Ling EA (1981) Ultrastructure and mode of formation of epiplexus cells in the choroid plexus in the lateral ventricles of the monkey (Macaca fascicularis). J Anat 133:555–569PubMedGoogle Scholar
  26. 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 41:43–56PubMedCrossRefGoogle Scholar
  27. Liu P, Hudson LC, Tompkins MB, Vahlenkamp TW, Colby B, Rundle C, Meeker RB (2006) Cerebrospinal fluid is an efficient route for establishing brain infection with feline immunodeficiency virus and transfering infectious virus to the periphery. J Neurovirol 12:294–306PubMedCrossRefGoogle Scholar
  28. 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 183:405–414PubMedGoogle Scholar
  29. 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 II antigens. J Neuroimmunol 40:173–182PubMedCrossRefGoogle Scholar
  30. Monken CE, Wu B, Srinivasan A (1995) High resolution analysis of HIV-1 quasispecies in the brain. AIDS 9:345–349PubMedGoogle Scholar
  31. Morris L, Silber E, Sonnenberg P, Eintracht S, Nyoka S, Lyons SF, Saffer D, Koornhof H, Martin DJ (1998) High human immunodeficiency virus type 1 RNA load in the cerebrospinal fluid from patients with lymphocytic meningitis. J Infect Dis 177:473–476PubMedCrossRefGoogle Scholar
  32. Morris A, Marsden M, Halcrow K, Hughes ES, Brettle RP, Bell JE, Simmonds P (1999) Mosaic structure of the human immunodeficiency virus type 1 genome infecting lymphoid cells and the brain: evidence for frequent in vivo recombination events in the evolution of regional populations. J Virol 73:8720–8731PubMedGoogle Scholar
  33. Nathanson JA, Chun LL (1989) Immunological function of the blood-cerebrospinal fluid barrier. Proc Natl Acad Sci USA 86:1684–1688PubMedCrossRefGoogle Scholar
  34. Neuenburg JK, Sinclair E, Nilsson A, Kreis C, Bacchetti P, Price RW, Grant RM (2004) HIV-Producing T Cells in Cerebrospinal Fluid. J Acquir Immune Defic Syndr 37:1237–1244PubMedCrossRefGoogle Scholar
  35. 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 5:670–677PubMedCrossRefGoogle Scholar
  36. Ritola K, Pilcher CD, Fiscus SA, Hoffman NG, Nelson JA, Kitrinos KM, Hicks CB, Eron JJ Jr, Swanstrom R (2004) Multiple V1/V2 env variants are frequently present during primary infection with human immunodeficiency virus type 1. J Virol 78:11208–11218PubMedCrossRefGoogle Scholar
  37. Ryan G, Klein D, Knapp E, Hosie MJ, Grimes T, Mabruk MJ, Jarrett O, Callanan JJ (2003) Dynamics of viral and proviral loads of feline immunodeficiency virus within the feline central nervous system during the acute phase following intravenous infection. J Virol 77:7477–7485PubMedCrossRefGoogle Scholar
  38. Ryan G, Grimes T, Brankin B, Mabruk MJ, Hosie MJ, Jarrett O, Callanan JJ (2005) Neuropathology associated with feline immunodeficiency virus infection highlights prominent lymphocyte trafficking through both the blood-brain and blood-choroid plexus barriers. J Neurovirol 11:337–345PubMedCrossRefGoogle Scholar
  39. Sasseville VG, Lackner AA (1997) Neuropathogenesis of simian immunodeficiency virus infection in macaque monkeys. J Neurovirol 3:1–9PubMedCrossRefGoogle Scholar
  40. Sei S, Stewart SK, Farley M, Mueller BU, Lane JR, Robb ML, Brouwers P, Pizzo PA (1996) Evaluation of human immunodeficiency virus (HIV) type 1 RNA levels in cerebrospinal fluid and viral resistance to zidovudine in children with HIV encephalopathy. J Infect Dis 174:1200–1206PubMedCrossRefGoogle Scholar
  41. Serot JM, Bene MC, Foliguet B, Faure GC (2000) Monocyte-derived IL-10-secreting dendritic cells in choroid plexus epithelium. J Neuroimmunol 105:115–119PubMedCrossRefGoogle Scholar
  42. Shacklett BL, Cox CA, Wilkens DT, Karl KR, Nilsson A, Nixon DF, Price RW (2004) Increased adhesion molecule and chemokine receptor expression on CD8+ T cells trafficking to cerebrospinal fluid in HIV-1 infection. J Infect Dis 189:2202–2212PubMedCrossRefGoogle Scholar
  43. Smit TK, Wang B, Ng T, Osborne R, Brew B, Saksena NK (2001) Varied tropism of HIV-1 isolates derived from different regions of adult brain cortex discriminate between patients with and without AIDS dementia complex (ADC): evidence for neurotropic HIV variants. Virology 279:509–526PubMedCrossRefGoogle Scholar
  44. Staprans S, Marlowe N, Glidden D, Novakovic-Agopian T, Grant RM, Heyes M, Aweeka F, Deeks S, Price RW (1999) Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS 13:1051–1061PubMedCrossRefGoogle Scholar
  45. 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 148:1819–1838PubMedGoogle Scholar
  46. Stevenson PG, Hawke S, Sloan DJ, Bangham CR (1997) The immunogenicity of intracerebral virus infection depends on anatomical site. J Virol 71:145–151PubMedGoogle Scholar
  47. Strain MC, Letendre S, Pillai SK, Russell T, Ignacio CC, Gunthard HF, Good B, Smith DM, Wolinsky SM, Furtado M, Marquie-Beck J, Durelle J, Grant I, Richman DD, Marcotte T, McCutchan JA, Ellis RJ, Wong JK (2005) Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy. J Virol 79:1772–1788PubMedCrossRefGoogle Scholar
  48. Thomas T, Stadler E, Dziadek M (1992) Effects of the extracellular matrix on fetal choroid plexus epithelial cells: changes in morphology and multicellular organization do not affect gene expression. Exp Cell Res 203:198–213PubMedCrossRefGoogle Scholar
  49. 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 296:259–269PubMedCrossRefGoogle Scholar
  50. Zheng W, Zhao Q, Graziano JH (1998) Primary culture of choroidal epithelial cells: characterization of an in vitro model of blood-CSF barrier. In Vitro Cell Dev Biol 34:40–45CrossRefGoogle Scholar
  51. Zink MC, Suryanarayana K, Mankowski JL, Shen A, Piatak M Jr, Spelman JP, Carter DL, Adams RJ, Lifson JD, Clements JE (1999) High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol 73:10480–10488PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Rick B. Meeker
    • 1
  • D. C. Bragg
    • 1
    • 3
  • Winona Poulton
    • 1
  • Lola Hudson
    • 2
  1. 1.Department of Neurology and Curriculum in NeurobiologyUniversity of North CarolinaChapel HillUSA
  2. 2.Department of Molecular Biomedical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  3. 3.Department of NeurologyMassachusetts General HospitalCharlestownUSA

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