Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1997 Nov;151(5):1341–1351.

Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection.

J B Rottman 1, K P Ganley 1, K Williams 1, L Wu 1, C R Mackay 1, D J Ringler 1
PMCID: PMC1858074  PMID: 9358760

Abstract

The chemokine receptor CCR5 has recently been described as a co-receptor for macrophage-tropic strains of human immunodeficiency virus (HIV)-1. In this study, using a panel of monoclonal antibodies specific for human CCR5, we show by immunohistochemistry and flow cytometry that CCR5 is expressed by bone-marrow-derived cells known to be targets for HIV-1 infection, including a subpopulation of lymphocytes and monocyte/macrophages in blood, primary and secondary lymphoid organs, and noninflamed tissues. In the central nervous system, CCR5 is expressed on neurons, astrocytes, and microglia. In other tissues, CCR5 is expressed on epithelium, endothelium, vascular smooth muscle, and fibroblasts. Chronically inflamed tissues contain an increased number of CCR5+ mononuclear cells, and the number of immunoreactive cells is directly associated with a histopathological correlate of inflammatory severity. Collectively, these results suggest that CCR5+ cells are recruited to inflammatory sites and, as such, may facilitate transmission of macrophage-tropic strains of HIV-1.

Full text

PDF
1341

Images in this article

1346Figure 5
on p.1346

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adachi A., Koenig S., Gendelman H. E., Daugherty D., Gattoni-Celli S., Fauci A. S., Martin M. A. Productive, persistent infection of human colorectal cell lines with human immunodeficiency virus. J Virol. 1987 Jan;61(1):209–213. doi: 10.1128/jvi.61.1.209-213.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alkhatib G., Combadiere C., Broder C. C., Feng Y., Kennedy P. E., Murphy P. M., Berger E. A. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996 Jun 28;272(5270):1955–1958. doi: 10.1126/science.272.5270.1955. [DOI] [PubMed] [Google Scholar]
  3. Angiolillo A. L., Sgadari C., Taub D. D., Liao F., Farber J. M., Maheshwari S., Kleinman H. K., Reaman G. H., Tosato G. Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med. 1995 Jul 1;182(1):155–162. doi: 10.1084/jem.182.1.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Armstrong J. A., Horne R. Follicular dendritic cells and virus-like particles in AIDS-related lymphadenopathy. Lancet. 1984 Aug 18;2(8399):370–372. doi: 10.1016/s0140-6736(84)90540-3. [DOI] [PubMed] [Google Scholar]
  5. Ayehunie S., Groves R. W., Bruzzese A. M., Ruprecht R. M., Kupper T. S., Langhoff E. Acutely infected Langerhans cells are more efficient than T cells in disseminating HIV type 1 to activated T cells following a short cell-cell contact. AIDS Res Hum Retroviruses. 1995 Aug;11(8):877–884. doi: 10.1089/aid.1995.11.877. [DOI] [PubMed] [Google Scholar]
  6. Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed] [Google Scholar]
  7. Becker S., Quay J., Koren H. S., Haskill J. S. Constitutive and stimulated MCP-1, GRO alpha, beta, and gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J Physiol. 1994 Mar;266(3 Pt 1):L278–L286. doi: 10.1152/ajplung.1994.266.3.L278. [DOI] [PubMed] [Google Scholar]
  8. Berkman N., Robichaud A., Krishnan V. L., Roesems G., Robbins R., Jose P. J., Barnes P. J., Chung K. F. Expression of RANTES in human airway epithelial cells: effect of corticosteroids and interleukin-4, -10 and -13. Immunology. 1996 Apr;87(4):599–603. doi: 10.1046/j.1365-2567.1996.477579.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bhat S., Spitalnik S. L., Gonzalez-Scarano F., Silberberg D. H. Galactosyl ceramide or a derivative is an essential component of the neural receptor for human immunodeficiency virus type 1 envelope glycoprotein gp120. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7131–7134. doi: 10.1073/pnas.88.16.7131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Biberfeld P., Chayt K. J., Marselle L. M., Biberfeld G., Gallo R. C., Harper M. E. HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy. Am J Pathol. 1986 Dec;125(3):436–442. [PMC free article] [PubMed] [Google Scholar]
  11. Cameron P. U., Lowe M. G., Sotzik F., Coughlan A. F., Crowe S. M., Shortman K. The interaction of macrophage and non-macrophage tropic isolates of HIV-1 with thymic and tonsillar dendritic cells in vitro. J Exp Med. 1996 Apr 1;183(4):1851–1856. doi: 10.1084/jem.183.4.1851. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chen Z., Zhou P., Ho D. D., Landau N. R., Marx P. A. Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J Virol. 1997 Apr;71(4):2705–2714. doi: 10.1128/jvi.71.4.2705-2714.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chesebro B., Buller R., Portis J., Wehrly K. Failure of human immunodeficiency virus entry and infection in CD4-positive human brain and skin cells. J Virol. 1990 Jan;64(1):215–221. doi: 10.1128/jvi.64.1.215-221.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Choe H., Farzan M., Sun Y., Sullivan N., Rollins B., Ponath P. D., Wu L., Mackay C. R., LaRosa G., Newman W. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell. 1996 Jun 28;85(7):1135–1148. doi: 10.1016/s0092-8674(00)81313-6. [DOI] [PubMed] [Google Scholar]
  15. Cocchi F., DeVico A. L., Garzino-Demo A., Arya S. K., Gallo R. C., Lusso P. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science. 1995 Dec 15;270(5243):1811–1815. doi: 10.1126/science.270.5243.1811. [DOI] [PubMed] [Google Scholar]
  16. Combadiere C., Ahuja S. K., Tiffany H. L., Murphy P. M. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES. J Leukoc Biol. 1996 Jul;60(1):147–152. doi: 10.1002/jlb.60.1.147. [DOI] [PubMed] [Google Scholar]
  17. Conaldi P. G., Serra C., Dolei A., Basolo F., Falcone V., Mariani G., Speziale P., Toniolo A. Productive HIV-1 infection of human vascular endothelial cells requires cell proliferation and is stimulated by combined treatment with interleukin-1 beta plus tumor necrosis factor-alpha. J Med Virol. 1995 Dec;47(4):355–363. doi: 10.1002/jmv.1890470411. [DOI] [PubMed] [Google Scholar]
  18. Craib K. J., Meddings D. R., Strathdee S. A., Hogg R. S., Montaner J. S., O'Shaughnessy M. V., Schechter M. T. Rectal gonorrhoea as an independent risk factor for HIV infection in a cohort of homosexual men. Genitourin Med. 1995 Jun;71(3):150–154. doi: 10.1136/sti.71.3.150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Dalgleish A. G., Beverley P. C., Clapham P. R., Crawford D. H., Greaves M. F., Weiss R. A. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984 Dec 20;312(5996):763–767. doi: 10.1038/312763a0. [DOI] [PubMed] [Google Scholar]
  20. Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di Marzio P., Marmon S., Sutton R. E., Hill C. M. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996 Jun 20;381(6584):661–666. doi: 10.1038/381661a0. [DOI] [PubMed] [Google Scholar]
  21. Dragic T., Litwin V., Allaway G. P., Martin S. R., Huang Y., Nagashima K. A., Cayanan C., Maddon P. J., Koup R. A., Moore J. P. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996 Jun 20;381(6584):667–673. doi: 10.1038/381667a0. [DOI] [PubMed] [Google Scholar]
  22. Edinger A. L., Amedee A., Miller K., Doranz B. J., Endres M., Sharron M., Samson M., Lu Z. H., Clements J. E., Murphey-Corb M. Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4005–4010. doi: 10.1073/pnas.94.8.4005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fauci A. S., Macher A. M., Longo D. L., Lane H. C., Rook A. H., Masur H., Gelmann E. P. NIH conference. Acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic, and therapeutic considerations. Ann Intern Med. 1984 Jan;100(1):92–106. doi: 10.7326/0003-4819-100-1-92. [DOI] [PubMed] [Google Scholar]
  24. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  25. Fox C. H., Tenner-Rácz K., Rácz P., Firpo A., Pizzo P. A., Fauci A. S. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991 Dec;164(6):1051–1057. doi: 10.1093/infdis/164.6.1051. [DOI] [PubMed] [Google Scholar]
  26. Furie M. B., Randolph G. J. Chemokines and tissue injury. Am J Pathol. 1995 Jun;146(6):1287–1301. [PMC free article] [PubMed] [Google Scholar]
  27. Gartner S., Markovits P., Markovitz D. M., Kaplan M. H., Gallo R. C., Popovic M. The role of mononuclear phagocytes in HTLV-III/LAV infection. Science. 1986 Jul 11;233(4760):215–219. doi: 10.1126/science.3014648. [DOI] [PubMed] [Google Scholar]
  28. Ho D. D., Neumann A. U., Perelson A. S., Chen W., Leonard J. M., Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995 Jan 12;373(6510):123–126. doi: 10.1038/373123a0. [DOI] [PubMed] [Google Scholar]
  29. Horuk R., Martin A. W., Wang Z., Schweitzer L., Gerassimides A., Guo H., Lu Z., Hesselgesser J., Perez H. D., Kim J. Expression of chemokine receptors by subsets of neurons in the central nervous system. J Immunol. 1997 Mar 15;158(6):2882–2890. [PubMed] [Google Scholar]
  30. Horuk R., Martin A., Hesselgesser J., Hadley T., Lu Z. H., Wang Z. X., Peiper S. C. The Duffy antigen receptor for chemokines: structural analysis and expression in the brain. J Leukoc Biol. 1996 Jan;59(1):29–38. doi: 10.1002/jlb.59.1.29. [DOI] [PubMed] [Google Scholar]
  31. Horuk R. Molecular properties of the chemokine receptor family. Trends Pharmacol Sci. 1994 May;15(5):159–165. doi: 10.1016/0165-6147(94)90077-9. [DOI] [PubMed] [Google Scholar]
  32. Koch A. E., Polverini P. J., Kunkel S. L., Harlow L. A., DiPietro L. A., Elner V. M., Elner S. G., Strieter R. M. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992 Dec 11;258(5089):1798–1801. doi: 10.1126/science.1281554. [DOI] [PubMed] [Google Scholar]
  33. Koenig S., Gendelman H. E., Orenstein J. M., Dal Canto M. C., Pezeshkpour G. H., Yungbluth M., Janotta F., Aksamit A., Martin M. A., Fauci A. S. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science. 1986 Sep 5;233(4768):1089–1093. doi: 10.1126/science.3016903. [DOI] [PubMed] [Google Scholar]
  34. Laga M., Manoka A., Kivuvu M., Malele B., Tuliza M., Nzila N., Goeman J., Behets F., Batter V., Alary M. Non-ulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: results from a cohort study. AIDS. 1993 Jan;7(1):95–102. doi: 10.1097/00002030-199301000-00015. [DOI] [PubMed] [Google Scholar]
  35. Liu R., Paxton W. A., Choe S., Ceradini D., Martin S. R., Horuk R., MacDonald M. E., Stuhlmann H., Koup R. A., Landau N. R. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996 Aug 9;86(3):367–377. doi: 10.1016/s0092-8674(00)80110-5. [DOI] [PubMed] [Google Scholar]
  36. Maher D., Hoffman I. Prevalence of genital infections in medical inpatients in Blantyre, Malawi. J Infect. 1995 Jul;31(1):77–78. doi: 10.1016/s0163-4453(95)91674-1. [DOI] [PubMed] [Google Scholar]
  37. Marcon L., Choe H., Martin K. A., Farzan M., Ponath P. D., Wu L., Newman W., Gerard N., Gerard C., Sodroski J. Utilization of C-C chemokine receptor 5 by the envelope glycoproteins of a pathogenic simian immunodeficiency virus, SIVmac239. J Virol. 1997 Mar;71(3):2522–2527. doi: 10.1128/jvi.71.3.2522-2527.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Meyer A., Coyle A. J., Proudfoot A. E., Wells T. N., Power C. A. Cloning and characterization of a novel murine macrophage inflammatory protein-1 alpha receptor. J Biol Chem. 1996 Jun 14;271(24):14445–14451. doi: 10.1074/jbc.271.24.14445. [DOI] [PubMed] [Google Scholar]
  39. Moses A. V., Nelson J. A. HIV infection of human brain capillary endothelial cells--implications for AIDS dementia. Adv Neuroimmunol. 1994;4(3):239–247. doi: 10.1016/s0960-5428(06)80262-7. [DOI] [PubMed] [Google Scholar]
  40. Nelson J. A., Wiley C. A., Reynolds-Kohler C., Reese C. E., Margaretten W., Levy J. A. Human immunodeficiency virus detected in bowel epithelium from patients with gastrointestinal symptoms. Lancet. 1988 Feb 6;1(8580):259–262. doi: 10.1016/s0140-6736(88)90348-0. [DOI] [PubMed] [Google Scholar]
  41. Parmentier H. K., van Wichen D. F., Meyling F. H., Goudsmit J., Schuurman H. J. Epitopes of human immunodeficiency virus regulatory proteins tat, nef, and rev are expressed in normal human tissue. Am J Pathol. 1992 Nov;141(5):1209–1216. [PMC free article] [PubMed] [Google Scholar]
  42. Perelson A. S., Neumann A. U., Markowitz M., Leonard J. M., Ho D. D. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996 Mar 15;271(5255):1582–1586. doi: 10.1126/science.271.5255.1582. [DOI] [PubMed] [Google Scholar]
  43. Ponath P. D., Qin S., Ringler D. J., Clark-Lewis I., Wang J., Kassam N., Smith H., Shi X., Gonzalo J. A., Newman W. Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. J Clin Invest. 1996 Feb 1;97(3):604–612. doi: 10.1172/JCI118456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rand M. L., Warren J. S., Mansour M. K., Newman W., Ringler D. J. Inhibition of T cell recruitment and cutaneous delayed-type hypersensitivity-induced inflammation with antibodies to monocyte chemoattractant protein-1. Am J Pathol. 1996 Mar;148(3):855–864. [PMC free article] [PubMed] [Google Scholar]
  45. Raport C. J., Gosling J., Schweickart V. L., Gray P. W., Charo I. F. Molecular cloning and functional characterization of a novel human CC chemokine receptor (CCR5) for RANTES, MIP-1beta, and MIP-1alpha. J Biol Chem. 1996 Jul 19;271(29):17161–17166. doi: 10.1074/jbc.271.29.17161. [DOI] [PubMed] [Google Scholar]
  46. Reimann K. A., Tenner-Racz K., Racz P., Montefiori D. C., Yasutomi Y., Lin W., Ransil B. J., Letvin N. L. Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques. J Virol. 1994 Apr;68(4):2362–2370. doi: 10.1128/jvi.68.4.2362-2370.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Reinhold M. I., Lindberg F. P., Kersh G. J., Allen P. M., Brown E. J. Costimulation of T cell activation by integrin-associated protein (CD47) is an adhesion-dependent, CD28-independent signaling pathway. J Exp Med. 1997 Jan 6;185(1):1–11. doi: 10.1084/jem.185.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Samson M., Labbe O., Mollereau C., Vassart G., Parmentier M. Molecular cloning and functional expression of a new human CC-chemokine receptor gene. Biochemistry. 1996 Mar 19;35(11):3362–3367. doi: 10.1021/bi952950g. [DOI] [PubMed] [Google Scholar]
  49. Schall T. J., Bacon K. B. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immunol. 1994 Dec;6(6):865–873. doi: 10.1016/0952-7915(94)90006-x. [DOI] [PubMed] [Google Scholar]
  50. Shezen E., Okon E., Ben-Hur H., Abramsky O. Cytokeratin expression in human thymus: immunohistochemical mapping. Cell Tissue Res. 1995 Jan;279(1):221–231. doi: 10.1007/BF00300707. [DOI] [PubMed] [Google Scholar]
  51. Spiegel H., Herbst H., Niedobitek G., Foss H. D., Stein H. Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells. Am J Pathol. 1992 Jan;140(1):15–22. [PMC free article] [PubMed] [Google Scholar]
  52. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  53. Takahashi K., Wesselingh S. L., Griffin D. E., McArthur J. C., Johnson R. T., Glass J. D. Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol. 1996 Jun;39(6):705–711. doi: 10.1002/ana.410390606. [DOI] [PubMed] [Google Scholar]
  54. Van Meir E., Ceska M., Effenberger F., Walz A., Grouzmann E., Desbaillets I., Frei K., Fontana A., de Tribolet N. Interleukin-8 is produced in neoplastic and infectious diseases of the human central nervous system. Cancer Res. 1992 Aug 15;52(16):4297–4305. [PubMed] [Google Scholar]
  55. Vazeux R., Brousse N., Jarry A., Henin D., Marche C., Vedrenne C., Mikol J., Wolff M., Michon C., Rozenbaum W. AIDS subacute encephalitis. Identification of HIV-infected cells. Am J Pathol. 1987 Mar;126(3):403–410. [PMC free article] [PubMed] [Google Scholar]
  56. Wiley C. A., Belman A. L., Dickson D. W., Rubinstein A., Nelson J. A. Human immunodeficiency virus within the brains of children with AIDS. Clin Neuropathol. 1990 Jan-Feb;9(1):1–6. [PubMed] [Google Scholar]
  57. Williams K. C., Dooley N. P., Ulvestad E., Waage A., Blain M., Yong V. W., Antel J. P. Antigen presentation by human fetal astrocytes with the cooperative effect of microglia or the microglial-derived cytokine IL-1. J Neurosci. 1995 Mar;15(3 Pt 1):1869–1878. doi: 10.1523/JNEUROSCI.15-03-01869.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Zhu T., Mo H., Wang N., Nam D. S., Cao Y., Koup R. A., Ho D. D. Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science. 1993 Aug 27;261(5125):1179–1181. doi: 10.1126/science.8356453. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES