The ability of HIV-1 to use dendritic cells (DCs) for transport and to transfer virus to activated T cells in the lymph node may be crucial in early HIV-1 pathogenesis. We have characterized primary DCs for the receptors involved in viral envelope attachment and observed that C-type lectin receptor (CLR) binding was predominant in skin DCs, whereas binding to emigrating and tonsil DCs was CD4-dependent. No one CLR was solely responsible for envelope binding on all skin DC subsets. DC-SIGN (DC-specific ICAM-3–grabbing nonintegrin) was only expressed by CD14+CDlalo dermal DCs. The mannose receptor was expressed by CD1ahi and CD14+CDlalo dermal DCs, and langerin was expressed by Langerhans cells. The diversity of CLRs able to bind HIV-1 in skin DCs may reflect their ability to bind a range of microbial glycoproteins.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Cameron, P.U. et al. Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science 257, 383–387 (1992).
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).
Pinchuk, L.M., Polacino, P.S., Agy, M.B., Klaus, S.J. & Clark, E.A. The role of CD40 and CD80 accessory cell molecules in dendritic cell-dependent HIV-1 infection. Immunity 1, 317–325 (1994).
Kawamura, T. et al. Candidate microbicides block HIV-1 infection of human immature langerhans cells within epithelial tissue explants. J. Exp. Med. 192, 1491–1500 (2000).
Reece, J.C. et al. HIV-1 selection by epidermal dendritic cells during transmission across human skin. J. Exp. Med. 187, 1623–1631 (1998).
Hu, J., Gardner, M.B. & Miller, C.J. Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J. Virol. 74, 6087–6095 (2000).
Spira, A.I. et al. Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J. Exp. Med. 183, 215–225 (1996).
Zhang, Z. et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells. Science 286, 1353–1357 (1999).
Stahl-Hennig, C. et al. Rapid infection of oral mucosal-associated lymphoid tissue with simian immunodeficiency virus. Science 285, 1261–1265 (1999).
Masurier, C. et al. Dendritic cells route human immunodeficiency virus to lymph nodes after vaginal or intravenous administration to mice. J. Virol. 72, 7822–7829 (1998).
Berger, E.A. et al. A new classification for HIV-1. Nature 391, 240 (1998).
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).
Dezutter-Dambuyant, C. et al. Interaction of human epidermal Langerhans cells with HIV-1 viral envelope proteins (gp 120 and gp 160s) involves a receptor-mediated endocytosis independent of the CD4 T4A epitope. J. Dermatol. 18, 377–392 (1991).
Geijtenbeek, T.B. et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587–597 (2000).
Turville, S.G. et al. HIV gp120 receptors on human dendritic cells. Blood 98, 2482–2488 (2001).
Turville, S.G. et al. Bitter-sweet symphony: defining the role of dendritic cell gp120 receptors in HIV infection. J. Clin. Virol. 22, 229–239 (2001).
Curtis, B.M., Scharnowske, S. & Watson, A.J. Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120. Proc. Natl. Acad. Sci. USA 89, 8356–8360 (1992).
Lenz, A., Heine, M., Schuler, G. & Romani, N. Human and murine dermis contain dendritic cells. Isolation by means of a novel method and phenotypical and functional characterization. J. Clin. Invest. 92, 2587–2596 (1993).
Nestle, F.O., Zheng, X.G., Thompson, C.B., Turka, L.A. & Nickoloff, B.J. Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J. Immunol. 151, 6535–6545 (1993).
Valladeau, J. et al. Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 12, 71–81 (2000).
McLellan, A.D., Heiser, A., Sorg, R.V., Fearnley, D.B. & Hart, D.N. Dermal dendritic cells associated with T lymphocytes in normal human skin display an activated phenotype. J. Invest. Dermatol. 111, 841–849 (1998).
Hladik, F. et al. Dendritic cell-T-cell interactions support coreceptor-independent human immunodeficiency virus type 1 transmission in the human genital tract. J. Virol. 73, 5833–5842 (1999).
Geijtenbeek, T.B. et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell. 100, 575–585 (2000).
Grassi, F. et al. Monocyte-derived dendritic cells have a phenotype comparable to that of dermal dendritic cells and display ultrastructural granules distinct from Birbeck granules. J. Leukoc. Biol. 64, 484–493 (1998).
Hart, D.N. Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 90, 3245–3287 (1997).
Romani, N. et al. Presentation of exogenous protein antigens by dendritic cells to T cell clones. Intact protein is presented best by immature, epidermal Langerhans cells. J. Exp. Med. 169, 1169–1178 (1989).
Sallusto, F., Cella, M., Danieli, C. & Lanzavecchia, A. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 182, 389–400 (1995).
Dezutter-Dambuyant, C. In vivo and in vitro infection of human Langerhans cells by HIV-1. Adv. Exp. Med. Biol. 378, 447–451 (1995).
Pohlmann, S. et al. DC-SIGN interactions with human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus. J. Virol. 75, 4664–4672 (2001).
Lee, B. et al. cis Expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J. Virol. 75, 12028–12038 (2001).
Soilleux, E.J., Barten, R. & Trowsdale, J. DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13. J. Immunol. 165, 2937–2942 (2000).
Soilleux, E.J. & Coleman, N. Langerhans cells and the cells of Langerhans cell histiocytosis do not express DC-SIGN. Blood 98, 1987–1988 (2001).
Soilleux, E.J. et al. Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J. Leukoc. Biol. 71, 445–457 (2002).
Mukhtar, M. et al. Primary isolated human brain microvascular endothelial cells express diverse HIV/SIV-associated chemokine coreceptors and DC-SIGN and L-SIGN. Virology 297, 78–88 (2002).
Kato, M. et al. Expression of multilectin receptors and comparative FITC-dextran uptake by human dendritic cells. Int. Immunol. 12, 1511–1519 (2000).
MacDonald, K.P.A. et al. Peripheral blood dendritic cell heterogeneity. Blood doi:10:1182/blood-2002-11-0097 (in the press, 2002).
MacDonald, K.P.A., Munster, D.J., Clark, G.J., Vuckovic, S. & Hart, D.N.J. in Leucocyte Typing VII (ed. Mason, D.) edn. 7 (Oxford University Press, Oxford, 2002).
Cameron, P., Pope, M., Granelli-Piperno, A. & Steinman, R.M. Dendritic cells and the replication of HIV-1. J. Leukoc. Biol. 59, 158–171 (1996).
Granelli-Piperno, A., Finkel, V., Delgado, E. & Steinman, R.M. Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells. Curr. Biol. 9, 21–29 (1999).
Pope, M., Gezelter, S., Gallo, N., Hoffman, L. & Steinman, R.M. 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).
Mahnke, K. et al. The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation via major histocompatibility complex class II-positive lysosomal compartments. J. Cell. Biol. 151, 673–684 (2000).
Engering, A. et al. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J. Immunol. 168, 2118–2126 (2002).
Stent, G. et al. Heterogeneity of freshly isolated human tonsil dendritic cells demonstrated by intracellular markers, phagocytosis, and membrane dye transfer. Cytometry 48, 167–176 (2002).
Chakrabarti, S., Sisler, J.R. & Moss, B. Compact, synthetic, vaccinia virus early/late promoter for protein expression. Biotechniques 23, 1094–1097 (1997).
Hoffman, T.L. et al. Stable exposure of the coreceptor-binding site in a CD4-independent HIV-1 envelope protein. Proc. Natl. Acad. Sci. USA 96, 6359–6364 (1999).
Pohlmann, S. et al. DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proc. Natl. Acad. Sci. USA 98, 2670–2675 (2001).
Taylor, M.E. & Drickamer, K. Structural requirements for high affinity binding of complex ligands by the macrophage mannose receptor. J. Biol. Chem. 268, 399–404 (1993).
Lewin, S.R. et al. Use of real-time PCR and molecular beacons to detect virus replication in human immunodeficiency virus type 1-infected individuals on prolonged effective antiretroviral therapy. J. Virol. 73, 6099–6103 (1999).
Endres, M.J. et al. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell 87, 745–756 (1996).
Supported by the Australian National Centre for HIV Virology Research (A. L. C.); an Australian Postgraduate Award (to S. T.); an Australian National Health and Medical Research Council grant (to P. U. C.); an NIH MSTP grant (to P. U. C.); a Wellcome trust and ANZ trustees grant (to P. U. C.); the Deutsche Forschungsgemeinschaft (S. P.); NIH grants R0140880 and R0135383 (to R. D.); a Burroughs Wellcome Fund translational research award (to R. W. D.); and an Elizabeth Glaser Scientist award from the Pediatric AIDS Foundation (to R. W. D.). Thanks to R. Berkowicz for tonsils, the staff of the VPSU for normal skin, to M. Taylor and D. Hart for cells and reagents and C. Wolczak for processing the manuscript.
The authors declare no competing financial interests.
About this article
Cite this article
Turville, S., Cameron, P., Handley, A. et al. Diversity of receptors binding HIV on dendritic cell subsets. Nat Immunol 3, 975–983 (2002). https://doi.org/10.1038/ni841
Nature Communications (2021)
Antiretroviral therapy partially improves the abnormalities of dendritic cells and lymphoid and myeloid regulatory populations in recently infected HIV patients
Scientific Reports (2019)
Current HIV/AIDS Reports (2019)
Nature Communications (2016)
Immunologic Research (2016)