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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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).
The authors declare no competing financial interests.
LCs are a natural barrier against HIV-1 transmission. (PDF 835 kb)
Immature LCs inhibit T cell infection. (PDF 162 kb)
The novel HIV-1 blocking antibody 10E2 stains Langerin on LCs in situ. (PDF 858 kb)
Primary emigrant LCs resemble immature isolated LCs. (PDF 177 kb)
Langerin binds HIV-1 gp120 and inhibits LC infection. (PDF 836 kb)
Lewis X is a potential microbicide that blocks HIV-1 gp120 binding to DC-SIGN, but not Langerin. (PDF 101 kb)
Summary of data obtained with different donors for LC isolation (PDF 8 kb)
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de Witte, L., Nabatov, A., Pion, M. et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med 13, 367–371 (2007). https://doi.org/10.1038/nm1541
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