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Langerin is a natural barrier to HIV-1 transmission by Langerhans cells

Nature Medicine volume 13, pages 367371 (2007) | Download Citation

Abstract

Human immunodeficiency virus-1 (HIV-1) is primarily transmitted sexually. Dendritic cells (DCs) in the subepithelium transmit HIV-1 to T cells through the C-type lectin DC-specific intercellular adhesion molecule (ICAM)-3-grabbing nonintegrin (DC-SIGN). However, the epithelial Langerhans cells (LCs) are the first DC subset to encounter HIV-1. It has generally been assumed that LCs mediate the transmission of HIV-1 to T cells through the C-type lectin Langerin, similarly to transmission by DC-SIGN on dendritic cells (DCs). Here we show that in stark contrast to DC-SIGN, Langerin prevents HIV-1 transmission by LCs. HIV-1 captured by Langerin was internalized into Birbeck granules and degraded. Langerin inhibited LC infection and this mechanism kept LCs refractory to HIV-1 transmission; inhibition of Langerin allowed LC infection and subsequent HIV-1 transmission. Notably, LCs also inhibited T-cell infection by viral clearance through Langerin. Thus Langerin is a natural barrier to HIV-1 infection, and strategies to combat infection must enhance, preserve or, at the very least, not interfere with Langerin expression and function.

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Acknowledgements

We thank L. Colledge, R. Mebius and M. Litjens for their comments on the manuscript, S. Santegoets for helping to set up the MUTZ3 culture, P. Gallay (Scripps Research Institute) for providing us with the pseudotyped HIV-1 viruses and S. Saeland (Schering Plough) for the Langerin plasmid. We are grateful to the Boerhaave Clinic for providing us with essential materials. We thank E.-C. Park and B. Seed (US National Institutes of Health AIDS Research and Reference Reagent Program) for providing the pSyn gp120 IgG reagent. L.d.W., A.N. and M.A.W.P.d.J. were supported by grants from the Dutch Scientific Research program (VIDI NWO 917-46-367; NWO 912-04-025); A.N. was also supported by the Dutch AIDS Foundation (20005033).

Author information

Affiliations

  1. Department of Molecular Cell Biology and Immunology, VU University Medical Center, van de Boechorstraat 7, 1081BT Amsterdam, The Netherlands.

    • Lot de Witte
    • , Alexey Nabatov
    • , Donna Fluitsma
    • , Marein A W P de Jong
    • , Yvette van Kooyk
    •  & Teunis B H Geijtenbeek
  2. Department of Dermatology and Venereology, University Hospital of Geneva, 24 Rue Micheli-du-Crest, 1211 Geneva, Switzerland.

    • Marjorie Pion
    •  & Vincent Piguet
  3. Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, 1081HV Amsterdam, The Netherlands.

    • Tanja de Gruijl

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Contributions

L.d.W. designed, executed and interpreted most experiments and prepared the manuscript. A.N. generated viruses and helped with several experiments. M.P. generated the Langerin lentiviral construct under supervision of V.P., who also helped with the manuscript preparation. D.F. executed and interpreted the electron microscopy analysis. M.A.W.P.d.J. helped with LC isolations. T.d.G. contributed reagents and knowledge on LC isolation. Y.v.K. provided supervision and helped with the manuscript preparation. T.B.H.G. supervised all aspects of this study including study design, execution and interpretation, and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Teunis B H Geijtenbeek.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    LCs are a natural barrier against HIV-1 transmission.

  2. 2.

    Supplementary Fig. 2

    Immature LCs inhibit T cell infection.

  3. 3.

    Supplementary Fig. 3

    The novel HIV-1 blocking antibody 10E2 stains Langerin on LCs in situ.

  4. 4.

    Supplementary Fig. 4

    Primary emigrant LCs resemble immature isolated LCs.

  5. 5.

    Supplementary Fig. 5

    Langerin binds HIV-1 gp120 and inhibits LC infection.

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    Supplementary Fig. 6

    Lewis X is a potential microbicide that blocks HIV-1 gp120 binding to DC-SIGN, but not Langerin.

  7. 7.

    Supplementary Table 1

    Summary of data obtained with different donors for LC isolation

  8. 8.

    Supplementary Methods

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DOI

https://doi.org/10.1038/nm1541

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