Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: Implications for HIV primary infection


Transmission of HIV-1 is predominantly restricted to macrophage (MΦ)-tropic strains. Langerhans ceils (LCs) in mucosal epithelium, as well as macrophages located in the submucosal tissues, may be initial targets for HIV-1. This study was designed to determine whether restricted transmission of HIV-1 correlates with expression and function of HIV-1 co-receptors on LCs and macrophages. Using polyclonal rabbit IgCs specific for the HIV co-receptors cytokines CXCR4 and CCR5, we found that freshly isolated epidermal LCs (resembling resident mucosal LCs) expressed CCR5, but not CXCR, on their surfaces. In concordance with surface expression, fresh LCs fused with Mφ -tropic but not with T-tropic HIV-1 envelopes. However, fresh LCs did contain intracellular CXCR4 protein that was transported to the surface during in vitro culture. Macrophages expressed high levels of both co-receptors on their surfaces, but only CCR5 was functional in a fusion assay. These data provide several possible explanations for the selective transmission of Mφ-tropic HIV variants and for the resistance to infection conferred by the CCR5 deletion.

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  1. 1

    Zhu, T. et al. Genotypic and phenotypic characterization of HIV-1 in patients with primary infection. Science 261, 1179–1181 (1993).

  2. 2

    Wolinsky, S.M. et al. Selective transmission of human immunodeficiency virus type 1 variants from mothers to infants. Science 255, 1134–1137 (1992).

  3. 3

    Zhu, T. et al. Genetic characterization of human immunodeficiency virus type 1 in blood and genital secretions: Evidence for viral compartmentalization and selection during sexual transmission. J. Vlrol. 70, 3098–3107 (1996).

  4. 4

    Zhang, L. et al. Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection. J. Virol. 67, 3354–3356 (1993).

  5. 5

    van't Wout, A.B. et al. Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J. Clin. Invest. 94, 2060–2067 (1994).

  6. 6

    Blauvelt, A. The role of skin dendritic cells in the initiation of HIV infection. Am. J. Med. 102(5B), 16–20 (1997).

  7. 7

    Cameron, P., Pope, M., Granelli-Piperno, A. & Steinman, R.M. Dendritic cells and the replication of HIV-1. J. Leukocyte Biol. 59, 158–171 (1996).

  8. 8

    Zambruno, G., Gianetti, A., Bertazzoni, U. & Girolomoni, G. Langerhans cells and HIV-1 infection. Immunol. Today 16, 520–524 (1995).

  9. 9

    Spira, A.I. et al. Cellular targets of infection and route of viral dissemination after an in-travaginal inoculation of simian immunodeficiency virus into rhesus macaques. J. Exp. Med. 183, 215–225 (1996).

  10. 10

    Miller, C.J. et al. Mechanism of genital transmission of SIV: A hypothesis based on transmission studies and the location of SIV in the genital tract of chronically infected female rhesus macaques. J. Med. Primatol. 21, 64–68 (1992).

  11. 11

    Granelli-Piperno, A. et al. Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine receptors. J. Exp. Med. 184, 2433–2438 (1996).

  12. 12

    Blauvelt, A. et al. Productive infection of dendritic cells by HIV-1 and their ability to capture virus are mediated through separate pathways. J. Clin. Invest. 100, 2043–2053 (1997).

  13. 13

    Pope, M. et al. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell 78, 389–398 (1994).

  14. 14

    Pope, M. et al. Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells. J. Exp. Med. 182, 2045–2056 (1995).

  15. 15

    Soto-Ramirez, L.E. et al. HIV-1 Langerhans cell tropism associated with heterosexual transmission of HIV. Science 271, 1291–1293 (1996).

  16. 16

    Steinman, R.M. The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol. 9, 271–276 (1991).

  17. 17

    Romani, N. et al. Cultured human Langerhans ceils resemble lymphoid dendritic cells in phenotype and function. J. Invest. Dermatol. 93, 600–609 (1989).

  18. 18

    Romani, N. & Schuler, G. The immunologic properties of epidermal Langerhans cells as part of the dendritic cell system. Springer Semin. Immunopathol. 13, 265–279 (1992).

  19. 19

    Sallusto, F. & Lanzavecchia, A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α. J. Exp. Med. 179, 1109–1118 (1994).

  20. 20

    Romani, N. et al. Proliferating dendritic cell progenitors in human blood. J. Exp. Med. 180, 83–93 (1994).

  21. 21

    Aiba, S. & Katz, S.I. Phenotypic and functional characteristics of in vivo-activated Langerhans ceils. J. Immunol. 145, 2791–2796 (1990).

  22. 22

    Kripke, M.L., Dunn, C.G., Jeevan, A., Tang, J. & Bucana, C. Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization. J. Immunol. 145, 2833–2838 (1990).

  23. 23

    Parr, M.B., Kepple, L. & Parr, E.L. Antigen recognition in the reproductive tract. II. Endocytosis of horseradish peroxidase by Langerhans cells in murine vaginal epithelium. Biol. Reprod. 45, 261–265 (1991).

  24. 24

    Edwards, J.N.T. & Morris, H.B. Langerhans' cells and lymphocyte subsets in the female genital tract. Br. J. Obstet. Gynecol. 92, 974–982 (1985).

  25. 25

    Miller, C.J., McGee, J.R. & Gardner, M.B. Biology of disease: Mucosal immunity, HIV transmission, and AIDS. Lab. Invest. 68, 129–145 (1993).

  26. 26

    Miller, C.J., McChesney, M. & Moore, P.F. Langerhans cells, macrophages, and lymphocyte subsets in the cervix and vagina of rhesus macaques. Lab. Invest. 67, 628–634 (1992).

  27. 27

    Lapham, C.K. et al. Evidence for cell-surface association between fusin and the CD4-gpl20 complex in human cell lines. Science 274, 602–605 (1996).

  28. 28

    Lusso, P. et al. Growth of macrophage-tropic and primary human immunodeficiency virus type 1 (HIV-1) isolates in a unique CD4+ T-cell clone (PM1): Failure to downregulate CD4 and to interfere with T-cell-line-tropic HIV-1. J. Virol. 69, 3712–3720 (1995).

  29. 29

    Endres, M.J. et al. CD4-independent infection by HIV-2 is mediated by CXCR-4. Cell 87, 745–756 (1996).

  30. 30

    Blauvelt, A. et al. Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons. J. Immunol. 154, 3506–3515 (1995).

  31. 31

    Broder, C.C., Dimitrov, D.S., Blumenthal, R. & Berger, E.A. The block to HIV-1 envelope glycoprotein-mediated membrane fusion in animal cells expressing human CD4 can be overcome by human cell components. Virology 193, 483–491 (1993).

  32. 32

    Pomerantz, R. et al. Human immunodeficiency virus (HIV) infection of the uterine cervix. Ann. Intern. Med. 108, 321–327 (1988).

  33. 33

    Nuovo, G., Forde, G., MacConnell, P. & Fahrenwald, R. In situ detection of PCR-ampli-fied HIV-1 nucleic acid and tumor necrosis factor cDNA in cervical tissues. Am. J. Pathol. 143, 40–48 (1993).

  34. 34

    Howell, A.L. et al. Human immunodeficiency virus type 1 infection of cells and tissues from the upper and lower human female reproductive tract. J. Virol. 71, 3498–3506 (1997).

  35. 35

    Macatonia, S.E., Patterson, S. & Knight, S.C. Suppression of immune responses by dendritic cells infected with HIV. Immunology 67, 285–289 (1989).

  36. 36

    Cameron, P.U. et al. Dendritic cells exposed to human immunodeficiency virus type 1 transmit a vigorous infection to CD4+ T cells. Science 257, 383–387 (1992).

  37. 37

    Weissman, D. et al. Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1. Proc. Natl: Acad. Sci. USA 92, 826–830 (1995).

  38. 38

    Berger, E.A. HIV entry and tropism: The chemokine receptor connection. AIDS 11 (Suppl. A) S3–S16 (1997).

  39. 39

    Orenstein, J.M., Fox, C. & Wahl, S. Macrophages as a source of HIV during opportunistic infections. Science 276, 1857–1861 (1997).

  40. 40

    Cameron, P.U. et al. The interaction of macrophage and non-macrophage tropic isolates of HIV-1 with thymic and tonsillar dendritic cells in vitro. J. Exp. Med. 183, 1851–1856 (1996).

  41. 41

    Liu, R. et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell 86, 367–377 (1996).

  42. 42

    Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CCR5 structural gene. Science 273, 1856–1862 (1996).

  43. 43

    Casamayor-Palleja, M., Khan, M. & MacLennan, I.C.M. A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J. Exp. Med. 181, 1293–1301 (1995).

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