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. 2006 Apr 5;11(3):306–312. doi: 10.1111/j.1750-3639.2001.tb00401.x

Crosstalk Between Components of the Blood Brain Barrier and Cells of the CNS in Microglial Activation in AIDS

Dianne Langford 2, Eliezer Masliah 1,2,✉
PMCID: PMC8098377  PMID: 11414473

Abstract

During the progression of AIDS, a majority of patients develop cognitive disorders such as HIV encephalitis (HIVE) and AIDS dementia complex (ADC), which correlate closely with macrophage infiltration into the brain and microglial activation. Microglial activation occurs in response to infection, inflammation and neurological disorders including HIVE, Alzheimer's disease, Parkinson's disease and multiple sclerosis. Microglia can be activated by immunoreactive cells independent of, but enhanced by HIV infection, from at least two routes. Activation may occur from signals originating from activated monocytes and lymphocytes in the blood stream, which initiate a cascade of stimuli that ultimately reach microglia in the brain or from activated macrophages/microglia/astrocytes within the brain. Effects of microglial activation stemming from both systemic and CNS HIV infection act together to commence signaling feedback, leading to HIVE and increased neurodegeneration. Most recent data indicate that in AIDS patients, microglial activation in the brain with subsequent release of excitotoxins, cytokines and chemokines leads to neurodegeneration and cognitive impairment. Since the presence of HIV in the brain results from migration of infected monocytes and lymphocytes across the vascular boundary, the development of novel therapies aimed at protecting the integrity of the blood brain barrier (BBB) upon systemic HIV infection is critical for controlling CNS infection.

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References

  • 1. Adamson DC, Wildemann B, Sasaki M, Glass JD, McArthur JC, Christov VI, Dawson TM, Dawson VL (1996) Immunologic NO synthase: elevation in severe AIDS dementia and induction by HIV‐1 gp41. Science 274: 1917–1921. [DOI] [PubMed] [Google Scholar]
  • 2. Bauer J, Huitinga I, Zhao W, Lassmann H, Hickey WF, Dijstra CD (1995) The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune disease encephalmyelitis. Glia 15: 437–446. [DOI] [PubMed] [Google Scholar]
  • 3. Bonwetsch R, Croul S, Richardson MW, Lorenzana C, Del Valle L, Sverstiuk AE, Amini S, Morgello S, Khalili K, Rappaport J (1999) Role of HIV‐1 Tat and CC chemokine MIP‐1 alpha in the pathogenesis of HIV‐associated central nervous system disorders. J Neurovirol 5: 685–694. [DOI] [PubMed] [Google Scholar]
  • 4. Boven LA, Gomes L, Hery C, Gray F, Verhoef J, Portegies P, Tardieu M, Nottet HS (1999) Increased peroxynitrite activity in AIDS dementia complex: Implications for the neuropathogenesis of HIV‐1 infection. J Immunol 162: 4319–4327. [PubMed] [Google Scholar]
  • 5. Boven LA, van der Bruggen T, Van Asbeck BS, Marx J, Nottet H (1999) Potential role of CCR5 polymorphism in the development of AIDS dementia complex. FEMS Immunol Med Microbiol 26: 243–247. [DOI] [PubMed] [Google Scholar]
  • 6. Boven LA, Middel J, Breij EC, Schotte D, Verhoef J, Soderland C, Nottet HS (2000) Interactions between HIV‐infected monocyte‐derived macrophages and human brain microvascular endothelial cells result in increased expression of CC chemokines. J Neurovirol 6: 382–389. [DOI] [PubMed] [Google Scholar]
  • 7. Boven LA, Middel J, Verhoef J, De Groot CJ, Nottet HS (2000) Monocyte infiltration is highly associated with loss of the tight junction protein zonula occludens in HIV‐1 associated dementia. Neuropathol Appl Neurobiol 26: 356–360. [DOI] [PubMed] [Google Scholar]
  • 8. Budka H, Wiley CA, Kleihues P, Artigas J, Ashbury AK, Cho E‐S, Cornblath DR (1991) HIV‐associated disease of the nervous system: Review of nomenclature and proposal for neuropathology‐based terminology. Brain Pathol 1: 143–152. [DOI] [PubMed] [Google Scholar]
  • 9. Bukrinsky MI, Nottet HS, Schmidtmayerova H, Schmidtmayerova H, Dubrovsky L, Flanagan CR, Mullins ME, Lipton SA, Gendelman HE (1995) Regulation of nitric oxide synthase activity in human immunodeficiency virus type‐1 (HIV‐1)‐infected monocytes: implications for HIV‐associated neurological disease. J Exp Med 181: 735–745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Cannella B, Cross AH, Raine CD (1990) Upregulationa nd coexpression oof adhesion molecules correlates with relapsing autoimmune demylination in the central nervous system. J Exp Med 172: 1521–1524. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Carlos T, Kovach N, Schwartz B, Rosa M, Newman B, Wayner E, Benjamin C, Osborn L, Lobb R, Harlan J (1991) Human monocytes bind to two cytokine‐induced adhesive ligands on cultured human endothelial cells: endothelial‐leukocyte adhesion molecule‐1 and vascular cell adhesion molecule‐1. Blood 77: 2266–2271. [PubMed] [Google Scholar]
  • 12. Conant K, Ma M, Nath A, Major EO (1996) Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF‐kappa B binding and protein kinase C activity in primary human astrocytes. J Virol 70: 1384–1389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Cota M, Kleinschmidt A, Ceccherini‐Silberstein F, Aloisi F, Mengozzi M, Mantovani A, Brack‐Werner R, Poli G (2000) Upregulated expression of interleukin‐8, RANTES and chemokine receptors in human astrocytic cells infected with HIV‐1. J Neurovirol 6: 75–83. [DOI] [PubMed] [Google Scholar]
  • 14. Dallasta LM, Pisarov LA, Esplen JE, Werley JV, Moses AV, Nelson JA, Achim CL (1999) Blood‐brain barrier tight junction disruption in human immunodeficiency virus‐1 encephalitis. Am J Pathol 155: 1915–1927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. DeLuca C, Kwon H, Lin R, Wainberg M, Hiscott J (1999) NF‐β activation and HIV‐1 induced apoptosis. Cyto Growth Fact Rev 10: 235–253. [DOI] [PubMed] [Google Scholar]
  • 16. Dhawan S, Weeks BS, Soderland C, Schnaper HW, Toro LA, Asthana SP, Hewlett IK, Stetler‐Stevenson G, Yamada KM, Meltzer MS (1995) HIV‐1 infection alters monocyte interactions with human microvascular endothelial cells. J Immunol 154: 422–432. [PubMed] [Google Scholar]
  • 17. Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan C (1993) Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease. Glia 7: 75–83. [DOI] [PubMed] [Google Scholar]
  • 18. Dobrogowska DH, Lossinsky AS, Tarnawski M, Vorbrodt AW (1998) Increased blood‐brain barrier permeability and endothelial abnormalities induced by vascular endothelial growth factor. J Neurocytol 27: 163–173. [DOI] [PubMed] [Google Scholar]
  • 19. Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, Brew BJ (1999) Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 13(10): 1249–1253. [DOI] [PubMed] [Google Scholar]
  • 20. Eder C (1998) Ion channels in microglia (brain macrophages). Am J Physiol 275: C327–C342. [DOI] [PubMed] [Google Scholar]
  • 21. Epstein LG, Gelbard HA (1999) HIV‐1 induced neuronal injury in the developing brain. J Leukoc Biol 65: 453–457. [DOI] [PubMed] [Google Scholar]
  • 22. Gebicke‐Haerter PJ, Van Calker D, Norenberg W, Illes P (1996) Molecular mechanisms of microglial activation: Implications for regeneration and neurodegenerative diseases. Neurochem Int 29: 1–12. [PubMed] [Google Scholar]
  • 23. Glass JD, Wesselingh SL, Selnes OA, McArthur JC (1993) Clinical‐neuropathological correlations in HIV‐associated dementia. Neurology 43: 2230–2237. [DOI] [PubMed] [Google Scholar]
  • 24. He J, Chen Y, Farzan M, Choe H, Ohagen A, Gartner S, Busciglio JJ, Yang X, Hofmann W, Newman W, Mackay CR, Sodroski J, Gabuzda D (1997) CCR3 and CCR5 are co‐receptors for HIV‐1 infection in microglia. Nature 385(6617): 645–49. [DOI] [PubMed] [Google Scholar]
  • 25. Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH, McCutchan JA, Taylor MJ, Kelly MD, Ellis RJ, Wolfson T, Velin R, Marcotte TD, Hesselink JR, Jernigan TL, Cahndler J, Wallace M, Abramson I, Group HNRC (1995) The HNRC‐500‐ neuropsychology of HIV infection at different disease stages. J Int Neuropsych Soc 1: 231–251. [DOI] [PubMed] [Google Scholar]
  • 26. Hurwitz AA, Berman JW, Rashbaum WK, Lyman WD (1993) Human fetal astrocytes induce the expression of blood‐brain barrier specific proteins by autologous endothelial cells. Brain Res 625: 238–243. [DOI] [PubMed] [Google Scholar]
  • 27. Kaul M, Lipton SA (1999) Chemokines and activated macrophages in HIV gp120‐induced neuronal apoptosis. Proc Natl Acad Sci USA 96: 8212–8216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Kong LY, Wilson BC, McMillan MK, Bing G, Hudson PM, Hong JS (1996) The effects of the HIV‐1 envelope protein gp120 on the production of nitric oxide and proinflammatory cytokines in mixed glial cell cultures. Cell Immunol 172: 77–83. [DOI] [PubMed] [Google Scholar]
  • 29. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. TINS 19: 312–318. [DOI] [PubMed] [Google Scholar]
  • 30. Lassmann H, Rossler K, Zimprich F, Vass K (1991) Expression of adhesion molecules and histocompatibility antigens at the blood brain barrier. Brain Pathol 1: 115–123. [DOI] [PubMed] [Google Scholar]
  • 31. Lee SH, Soyoola E, Chanmugam P, Hart S, Sun W, Zhong H, Liou SS, Simmons D, Hwang D (1992) Elective expression of mitogen‐inducible cyclooxygenase in macrophages stimulated with lipopolysaccharide. J Biol Chem 267: 25934–25938. [PubMed] [Google Scholar]
  • 32. Levi G, Minghetti L, Alosi F (1998) Regulation of prostanoid synthesis in microglial cells and effects of prostaglandin E2 on microglial functions. Biochimie 80: 899–990. [DOI] [PubMed] [Google Scholar]
  • 33. Maehlen J, Dunlop O, Liestol K, Dobloug JH, Goplen AK, Torvik A (1995) Changing incidence of HIV‐induced brain lesions in Oslo, 1983–1994: effects of zidovudine treatment. AIDS 9: 1165–1169. [PubMed] [Google Scholar]
  • 34. Masliah E, Achim CL, Ge N, DeTeresa R, Terry RD, Wiley CA (1992) Spectrum of human immunodeficiency virus‐associated neocortical damage. Ann Neurol 32: 321–329. [DOI] [PubMed] [Google Scholar]
  • 35. McArthur JC, Grant I (1997). HIV Neurocognitive Disorders. In: The Neurology of AIDS, Gendelman HE, Lipton SA, Epstein L, Swindells S (eds.), Chapter 35 pp. 499–523, Chapman and Hall: New York , New York . [Google Scholar]
  • 36. McManus CM, Weidenheim K, Woodman SE, Nunez J, Hesselgesser J, Nath A, Berman JW (2000) Chemokine and chemokine‐receptor expression in human glial elements: induction by the HIV protein, and chemokine autoregulation. Am J Pathol 156: 1441–1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Michaels SH, Clark R, Kissinger P (1998) Declining morbidity and mortality among patients with advanced human immunodificiency virus infection. NEJM 339: 405–406. [DOI] [PubMed] [Google Scholar]
  • 38. Nottet HS, Persidsky Y, Sasseville VG, Nukuna AN, Bock P, Zhai QH, 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. [PubMed] [Google Scholar]
  • 39. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. NEJM 338: 853–860. [DOI] [PubMed] [Google Scholar]
  • 40. Pardridge WM (1999) Blood‐brain barrier biology and methodology. J Neurovirol 5: 556–569. [DOI] [PubMed] [Google Scholar]
  • 41. Persidsky Y, Stins M, Way D, Witte MH, Weinand M, Kim KS, Bock P, Gendelman HE, Fiala M (1997) A model of monocyte migration through the blood‐brain barrier during HIV‐1 encephalitis. J Immunol 158: 3499–3510. [PubMed] [Google Scholar]
  • 42. Persidsky Y, Ghorpade A, Rasmussen J, Limoges J, Liu XJ, Stins M, Fiala M, Way D. Kim KS, Witte MH, Weinanad M, Carhart L, Gendelman HE (1999) Microglial and astrocyte chemokines regulate monocyte migration through the blood‐brain barrier in human immunodeficiency virus‐1 encephalitis. Am J Pathol 155: 1599–1611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Polazzi E, Levi G, Minghetti L (1999) Human immunodeficiency virus type 1 Tat protein stimulates inducible nitric oxide synthase expression and nitric oxide production in microglial cultures. J Neuropathol Exp Neurol 58: 825–831. [DOI] [PubMed] [Google Scholar]
  • 44. Rosseler K, Neuchrist C, Kitz K, Scheiner O, Kraft D, Lassmann H (1992) Expression of leucocyte adhesion molecules at the human blood‐brain barrier (BBB). J Neurosci Res 31: 365–374. [DOI] [PubMed] [Google Scholar]
  • 45. Sasseville VG, Newman W, Brodie SJ, Hesterberg P, Pauley D, Ringler DJ (1994) Monocyte adhesion to endothelium in simian immunodeficiency virus‐induced AIDS encephalitis is mediated by vascular cell adhesion molecule‐1/alpha 4 beta 1 integrin interactions. Am J Pathol 144: 27–40. [PMC free article] [PubMed] [Google Scholar]
  • 46. Sharer LR (1992) Pathology of HIV‐1 infection of the central nervous system. A review. J Neuropathol Exp Neurol 51: 3–11. [DOI] [PubMed] [Google Scholar]
  • 47. Smits HA, Boven LA, Pereira CF, Verhoef J, Nottet S (2000) Role of macrophage activation in the pathogenesis of Alzheimer's disease and human immunodeficiency virus type I‐associated dementia. Eur J Clin Invest 30: 526–535. [DOI] [PubMed] [Google Scholar]
  • 48. Speth C, Joebstl B, Barcova M, Dierich MP (2000) HIV‐1 envelope protein gp41 modulates expression of inter‐leukin‐10 and chemokine receptors on monocytes, astrocytes and neurons. AIDS 14: 629–636. [DOI] [PubMed] [Google Scholar]
  • 49. Stollg G, Jander S (1999) The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 58: 2333–247. [DOI] [PubMed] [Google Scholar]
  • 50. Tan SV, Guiloff RJ (1998) Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psych 65: 23–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Toneatto S, Finco O, van der Putten H, Abrignani S, Annunziata P (1999) Evidence of blood‐brain barrier alteration and activation in HIV‐1 gp120 transgenic mice. AIDS 13: 2343–2348. [DOI] [PubMed] [Google Scholar]
  • 52. 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 63: 2953–2959. [PubMed] [Google Scholar]
  • 53. Westmoreland SV, Roottman JB, Williams AA, Lackner AA, Sasseville VG (1998) Chemokine receptor expression on resident and inflammatory cells in the brain of macaques with simian immunodeficiency virus encephalitis. Am J Pathol 152: 659–665. [PMC free article] [PubMed] [Google Scholar]
  • 54. Wiley CA, Achim CL, Christopherson C, Kidane Y, Kwok S, Masliah E, Mellors J, Radhakrishnan L, Wang G, Soon‐tornniyomkij V (1999) HIV mediates a productive infection of the brain. AIDS 13: 2055–2059. [DOI] [PubMed] [Google Scholar]
  • 55. Wiley CA, Achim C (1994) HIV encephalitis is the pathologic correlate of dementia in AIDS. Ann Neurol 36: 673–676. [DOI] [PubMed] [Google Scholar]
  • 56. Wiley CA, Schrier RD, Nelson JA, Lampert PW, Oldstone MB (1986) Cellular localization of human immunodeficiency virus infection within the brain of acquired immune deficiency syndrome patients. Proc Natl Acad Sci USA 83: 7089–7093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Williams KC, Hickey WF (1995) Traffick of hematogenous cells through the central nervous system In: HIV and Dementia, Oldstone MBA, Vitkovic L. (eds.), pp. 221–246, Springer‐Verlag, Berlin . [DOI] [PubMed] [Google Scholar]
  • 58. Wu DT, Woodman SE, Weiss JM, McManus CM, D'Aversa TG, Hesselgesser J, Major EO, Nath A, Berman JW (2000) Mechanisms of leukocyte trafficking into the CNS. J Neurovirol Suppl 1: S82–85. [PubMed] [Google Scholar]
  • 59. Yoshioka M, Bradley WG, Shapshak P, Nagano I, Stewart RV, Xin K‐Q, Srivastava AK, Nakamura S (1995) Role of immune activation and cytokine expression in HIV‐1‐associated neurologic diseases. Adv Neuroimmunol 5: 335–358. [DOI] [PubMed] [Google Scholar]

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