Skip to main content
PMC home page
Brain Pathology logoLink to Brain Pathology
. 2006 Apr 5;12(4):442–455. doi: 10.1111/j.1750-3639.2002.tb00461.x

Human Brain Parenchymal Microglia Express CD14 and CD45 and are Productively Infected by HIV‐1 in HIV‐1 Encephalitis

Melissa A Cosenza 1, Meng‐Liang Zhao 1, Qiusheng Si 1, Sunhee C Lee 1,✉
PMCID: PMC8095974  PMID: 12408230

Abstract

Microglia are endogenous brain macrophages that show distinct phenotypes such as expression of myeloid antigens, ramified morphology, and presence within the neural parenchyma. They play significant roles in a number of human CNS diseases including AIDS dementia. Together with monocytederived (perivascular) macrophages, microglia represent a major target of HIV‐1 infection. However, a recent report challenged this notion based on findings in SIV encephalitis. This study concluded that perivascular macrophages can be distinguished from parenchymal microglial cells by their expression of CD14 and CD45, and that macrophages, but not microglia, are productively infected in SIV and HIV encephalitis. To address whether parenchymal microglia are productively infected in HIV encephalitis, we analyzed expression of CD14, CD45 and HIV‐1 p24 in human brain. Microglia were identified based on their characteristic ramified morphology and location in the neural parenchyma. We found that parenchymal microglia are CD14+ (activated), CD45+ (resting and activated), and constitute approximately two thirds of the p24+ cells in HIV encephalitis cases. These results demonstrate that microglia are major targets of infection by HIV‐1, and delineate possible differences between HIVE and SIVE. Because productively infected tissue macrophages serve as the major viral reservoir, these findings have important implications for AIDS.

Full Text

The Full Text of this article is available as a PDF (796.6 KB).

References

  • 1. Albright AV, Shieh JT, O'Connor MJ, Gonzalez‐Scarano F (2000) Characterization of cultured microglia that can be infected by HIV‐1. J Neurovirol 6 Suppl 1:S53–S60. [PubMed] [Google Scholar]
  • 2. Albright AV, Shieh JTC, Itoh T, Lee B, Pleasure D, O'Connor MJ, Doms RW, Gonzalez‐Scarano F (1999) Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J Virol 73:205–213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Becher B, Fedorowicz V, Antel JP (1996) Regulation of CD14 expression on human adult central nervous systemderived microglia. J Neurosci Res 45:375–381. [DOI] [PubMed] [Google Scholar]
  • 4. Boche D, Gray F, Chakrabarti L, Hurtrel M, Montagnier L, Hurtrel B (1995) Low susceptibility of resident microglia to simian immunodeficiency virus replication during the early stages of infection. Neuropathol Appl Neurobiol 21:535–539. [DOI] [PubMed] [Google Scholar]
  • 5. Brew BJ, Rosenblum M, Cronin K, Price RW (1995) AIDS dementia complex and HIV‐1 brain infection: clinical‐virological correlations. Ann Neurol 38:563–570. [DOI] [PubMed] [Google Scholar]
  • 6. Briggs SD, Scholtz B, Jacque JM, Swingler S, Stevenson M, Smithgall TE (2001) HIV‐1 Nef promotes survival of myeloid cells by a Stat3‐dependent pathway. J Biol Chem 276:25605–25611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Brinkmann R, Schwinn A, Muller J, Stahl‐Hennig C, Coulibaly C, Hunsmann G, Czub S, Rethwilm A, Dorries R, Ter Meulen V (1993) In vitro and in vivo infection of rhesus monkey microglial cells by simian immunodeficiency virus. Virology 195:561–568. [DOI] [PubMed] [Google Scholar]
  • 8. Budka H (1990) Human immunodeficiency virus (HIV) envelope and core proteins in CNS tissues of patients with the acquired immune deficiency syndrome (AIDS). Acta Neuropathol (Berl) 79:611–619. [DOI] [PubMed] [Google Scholar]
  • 9. Dickson DW, Lee SC (1997) Microglia. Textbook of neuropathology. Edited by Davis RLand Robertson DM. Baltimore, Williams & Wilkins, pp. 165–205. [Google Scholar]
  • 10. Dickson DW, Lee SC, Hatch WC, Mattiace L, Brosnan CF, Lyman WD (1994) Macrophages and microglia in HIV‐1‐related CNS neuropathology. HIV, AIDS and the brain, ARNMD. Edited by Price RW and Perry SW. New York , Raven Press, pp. 99–118. [PubMed] [Google Scholar]
  • 11. Dickson DW, Mattiace LA, Kure K, Hutchins KD, Lyman WD, Brosnan CF (1991) Biology of disease: microglia in human disease, with an emphasis on the aquired immunodeficiency syndrome. Lab Invest 64:135–156. [PubMed] [Google Scholar]
  • 12. Gabuzda DH, Ho DD, de la Monte 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. [DOI] [PubMed] [Google Scholar]
  • 13. Gehrmann J, Matsumoto Y, Kreutzberg GW (1995) Microglia:intrinsic immune effector cell of the brain. Brain Res -Brain Res Rev 20:269–287. [DOI] [PubMed] [Google Scholar]
  • 14. Geleziunas R, Xu W, Takeda K, Ichijo H, Greene WC (2001) HIV‐1 Nef inhibits ASK1‐dependent death signalling providing a potential mechanism for protecting the infected host cell. Nature 410:834–838. [DOI] [PubMed] [Google Scholar]
  • 15. Giulian D (1987) Ameboid microglia as effector cells of inflammation in the central nervous system. J Neurosci Res 18:155. [DOI] [PubMed] [Google Scholar]
  • 16. Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995) Immunocytochemical quantification of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 38:755–762. [DOI] [PubMed] [Google Scholar]
  • 17. He J, Chen Y, Farzan M, Choe H, Ohagen A, Gartner S, Busciglio J, Yang X, Hofmann W, Newman W, Mackay CR, Sodroski J, Gabuzda D (1997) CCR3 and CCR5 are coreceptors for HIV‐1 infection of microglia. Nature 385:645–649. [DOI] [PubMed] [Google Scholar]
  • 18. Heidenreich S (1999) Monocyte CD14: a multifunctional receptor engaged in apoptosis from both sides. J Leukoc Biol 65:737–743. [DOI] [PubMed] [Google Scholar]
  • 19. Hickey WF, Kimura H (1988) Perivascular microglial cells of the CNS are bone marrow‐derived and present antigen in vivo. Science 239:290–292. [DOI] [PubMed] [Google Scholar]
  • 20. Hoffman TL, Doms RW (1998) Chemokines and coreceptors in HIV/SIV host interactions. AIDS 12:S17‐S26. [PubMed] [Google Scholar]
  • 21. Hurtrel B, Chakrabarti L, Hurtrel M, Montagnier L (1993) Target cells during early SIV encephalopathy. Res Virol 144:41–46. [DOI] [PubMed] [Google Scholar]
  • 22. Irie‐Sasaki J, Sasaki T, Matsumoto W, Opavsky A, Cheng M, Welstead G, Griffiths E, Krawczyk C, Richardson CD, Aitken K, Iscove N, Koretzky G, Johnson P, Liu P, Rothstein DM, Penninger JM (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409:349–354. [DOI] [PubMed] [Google Scholar]
  • 23. Jordan CA, Watkins BA, Kufka C, Dubois‐Dalq M (1991) Infection of brain microglial cells by human immunodeficiency virus type I is CD4 dependent. J Virol 65:736–742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Karp HL, Tillotson ML, Soria J, Reich C, Wood JG (1994) Microglial tyrosine phosphorylation systems in normal and degenerating brain. Glia 11:284–290. [DOI] [PubMed] [Google Scholar]
  • 25. Kitai R, Zhao ML, Zhang N, Hua LL, Lee SC (2000) Role of MIP‐1b and RANTES in HIV‐1 infection of microglia: inhibition of infection and induction by IFNb. J Neuroimmunol 110:230–239. [DOI] [PubMed] [Google Scholar]
  • 26. Kolson DL, Lavi E, Gonzalez‐Scarano F (1998) The effects of human immunodeficiency virus in the central nervous system. Adv Virus Res 50:1–47. [DOI] [PubMed] [Google Scholar]
  • 27. Kure K, Lyman WD, Weidenheim KM, Dickson DW (1990) Cellular localization of an HIV‐1 antigen in subacute AIDS encephalitis using an improved double‐labeling immunohistochemical method. Am J Pathol 136:1085–1092. [PMC free article] [PubMed] [Google Scholar]
  • 28. Lane TE, Buchmeier MJ, Watry DD, Jakubowski DB, Fox HS (1995) Serial passage of microglial SIV results in selection of homogeneous env quasispecies in the brain. Virology 212:458–465. [DOI] [PubMed] [Google Scholar]
  • 29. Lassman H, Hickey WF (1993) Dynamics of microglia in brain pathology: Radiation bone marrow chimeras as a tool to study microglia turnover in normal brain and inflammation. Clin Neuropathol 12:284–313. [PubMed] [Google Scholar]
  • 30. Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39:151–170. [DOI] [PubMed] [Google Scholar]
  • 31. Lee SC, Hatch WC, Liu W, Lyman WD, Kress Y, Dickson DW (1993) Productive infection of human fetal microglia by HIV‐1. Am J Pathol 143:1032–1039. [PMC free article] [PubMed] [Google Scholar]
  • 32. Lee SC, Kress Y, Zhao M‐L, Dickson DW, Casadevall A (1995) Cryptococcus neoformans survive and replicate in human microglia. Lab Invest 73:871–879. [PubMed] [Google Scholar]
  • 33. Lee SC, Liu W, Brosnan CF, Dickson DW (1992) Characterization of human fetal dissociated CNS cultures with an emphasis on microglia. Lab Invest 67:465–475. [PubMed] [Google Scholar]
  • 34. Lee SC, Liu W, Brosnan CF, Dickson DW (1994) GM‐CSF promotes proliferation of human fetal and adult microglia in primary cultures. Glia 12:309–318. [DOI] [PubMed] [Google Scholar]
  • 35. Lee SC, Liu W, Dickson DW, Brosnan CF, Berman JW (1993) Cytokine production by human fetal microglia and astrocytes: differential induction by LPS and IL‐1 b. J Immunol 150:2659–2667. [PubMed] [Google Scholar]
  • 36. Lipton SA, Gendelman HE (1995) Dementia associated with the acquired immunodeficiency syndrome. New Engl J Med 332:934–940. [DOI] [PubMed] [Google Scholar]
  • 37. Liu W, Brosnan CF, Dickson DW, Lee SC (1994) Macrophage colony stimulating factor mediates astrocyte‐induced microglial ramification in human fetal CNS culture. Am J Pathol 145:48–53. [PMC free article] [PubMed] [Google Scholar]
  • 38. Mahlknecht U, Herbein G (2001) Macrophages and Tcell apoptosis in HIV infection: a leading role for accessory cells Trends Immunol 22:256–260. [DOI] [PubMed] [Google Scholar]
  • 39. Masliah E, Mallory M, Hansen L, Alford M, Albright T, Terry R, Shapiro P, Sundsmo M, Saitoh T (1991) Immunoreactivity of CD45, a protein phosphotyrosine phosphatase, in Alzheimer's disease. Acta Neuropathol (Berl) 83:12–20. [DOI] [PubMed] [Google Scholar]
  • 40. Navia BA, Cho ES, Petito CK, Price RW (1986) The AIDS dementia complex. II. Neuropathology. Ann Neurol 17:271–284. [DOI] [PubMed] [Google Scholar]
  • 41. Navia BA, Jordan BD, Price RW (1986) The AIDS dementia complex. I. Clinical features. Ann Neurol 19:517–524. [DOI] [PubMed] [Google Scholar]
  • 42. Penninger JM, Irie‐Sasaki J, Sasaki T, Oliveira‐dos‐Santos AJ (2001) CD45: new jobs for an old acquaintance. Nat Immunol 2:389–396. [DOI] [PubMed] [Google Scholar]
  • 43. Perry VH, Gordon S (1988) Macrophages and microglia in the nervous system. Trends Neurosci 11:273–277. [DOI] [PubMed] [Google Scholar]
  • 44. Popovich PG, Hickey WF (2001) Bone marrow chimeric rats reveal the unique distribution of resident and recruited macrophages in the contused rat spinal cord. J Neuropathol Exp Neurol 60:676–685. [DOI] [PubMed] [Google Scholar]
  • 45. Raghavan R, Cheney PD, Raymond LA, Joag SV, Stephens EB, Adany I, Pinson DM, Li Z, Marcario JK, Jia F, Wang C, Foresman L, Berman NE, Narayan O (1999) Morphological correlates of neurological dysfunction in macaques infected with neurovirulent simian immunodeficiency virus. Neuropathol Appl Neurobiol 25:285–294. [DOI] [PubMed] [Google Scholar]
  • 46. Rich EA, Chen IS, Zack JA, Leonard ML, O'Brien WA (1992) Increased susceptibility of differentiated mononuclear phagocytes to productive infection with human immunodeficiency virus‐1 (HIV‐1). J Clinn Invest 89:176–183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Rostasy K, Monti L, Yiannoutsos C, Kneissl M, Bell J, Kemper TL, Hedreen JC, Navia BA (1999) Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. Ann Neurol 46:207–216. [PubMed] [Google Scholar]
  • 48. Santambrogio L, Belyanskaya SL, Fischer FR, Cipriani B, Brosnan CF, Ricciardi‐Castagnoli P, Stern LJ, Strominger JL, Riese R (2001) Developmental plasticity of CNS microglia. Proc Natl Acad Sci U S A 98:6295–6300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Scarlatti G, Tresoldi E, Bjorndal A, Fredriksson R, Colog‐nesi C, Deng HK, Malnati MS, Plebani A, Siccardi AG, Littman DR, Fenyo EM, Lusso P (1997) In vivo evolution of HIV‐1 co‐receptor usage and sensitivity to chemokine‐mediated suppression. Nat Med 3:1259–1265. [DOI] [PubMed] [Google Scholar]
  • 50. Schmidtmayerova H, Sherry B, Bukrinsky M (1996) Chemokines and HIV replication. Nature 382:767. [DOI] [PubMed] [Google Scholar]
  • 51. Schrager LK, D'Souza MP (1998) Cellular and anatomical reservoirs of HIV‐1 in patients receiving potent antiretroviral combination therapy. JAMA 280:67–71. [DOI] [PubMed] [Google Scholar]
  • 52. Sharkey ME, Teo I, Greenough T, Sharova N, Luzuriaga K, Sullivan JL, Bucy RP, Kostrikis LG, Haase A, Veryard C, Davaro RE et al (2000) Persistence of episomal HIV‐1 infection intermediates in patients on highly active antiretroviral therapy. Nat Med 6:76–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Swingler S, Mann A, Jacque J, Brichacek B, Sasseville VG, Williams K, Lackner AA, Janoff EN, Wang R, Fisher D, Stevenson M (1999) HIV‐1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nat Med 5:997–103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Tan J, Town T, Mori T, Wu Y, Saxe M, Crawford F, Mullan M (2000) CD45 opposes beta‐amyloid peptide‐induced microglial activation via inhibition of p44/42 mitogen‐activated protein kinase. J Neurosci 20:7587–7594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55. Ulevitch RJ, Tobias PS (1995) Receptor‐dependent mechanisms of cell stimulation by bacterial endotoxin. Annu Rev Immunol1 3:437–457. [DOI] [PubMed] [Google Scholar]
  • 56. Ulvestad E, Williams K, Mork S, Antel J, Nyland H (1994) Phenotypic differences between human monocytes/ macrophages and microglial cells studied in situ and in vitro. J Neuropathol Exp Neurol 53:492–501. [DOI] [PubMed] [Google Scholar]
  • 57. Unger ER, Sung JH, Manivel JC, Chenggis ML, Blazar BR, Krivit W (1993) Male donor‐derived cells in the brains of female sex‐mismatched bone marrow transplant recipients: a Y‐chromosome specific in situ hybridization study. J Neuropathol Exp Neurol 52:460–470. [DOI] [PubMed] [Google Scholar]
  • 58. Unutmaz D, KewalRamani VN, Littman DR (1998) G protein‐coupled receptors in HIV and SIV entry: new perspectives on lentivirus‐host interactions and on the utility of animal models. Semin Immunol 10:225–236. [DOI] [PubMed] [Google Scholar]
  • 59. Watkins BA, Dorn HH, Kelly WB, Armstrong RC, Potts BJ, Michaels F, Kufta CV, Dubois‐Dalq M (1990) Specific tro‐pism of HIV‐1 for microglial cells in primary human brain cultures. Science 249:549–553. [DOI] [PubMed] [Google Scholar]
  • 60. Weidenheim K, Epshteyn I, Lyman WD (1993) Immunocytochemical identification of T‐cells in HIV‐1 encephalitis: implications for pathogenesis of CNS disease. Mod Pathol 6:167–174. [PubMed] [Google Scholar]
  • 61. Williams K, Ulvestad E, Hickey WF (1994) Immunology of multiple sclerosis. Clin Neurosci 2:229–245. [PubMed] [Google Scholar]
  • 62. Williams KC, Corey S, Westmoreland SV, Pauley D, Knight H, de Bakker C, Alvarez X, Lackner AA (2001) Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropatho‐genesis of AIDS. J Exp Med 193:905–915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249:1431–1433. [DOI] [PubMed] [Google Scholar]
  • 64. Zhao ML, Kim MO, Morgello S, Lee SC (2001) Expression of iNOS, IL‐1 and caspase‐1 in HIV‐1 encephalitis. J Neuroimmunol 115:182–191. [DOI] [PubMed] [Google Scholar]
  • 65. Zink MC, Amedee AM, Mankowski JL, Craig L, Didier P, Carter DL, Munoz A, Murphey‐Corb M, Clements JE (1997) Pathogenesis of SIV encephalitis. Selection and replication of neurovirulent SIV. Am J Pathol 151:793–803. [PMC free article] [PubMed] [Google Scholar]
  • 66. 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 73:10480–10488. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Brain Pathology are provided here courtesy of Wiley

RESOURCES