title: Caveolin-1 mediated uptake via langerin restricts HIV-1 infection in human Langerhans cells.
abstract: BACKGROUND
  Human Langerhans cells (LCs) reside in foreskin and vaginal mucosa and are the first immune cells to interact with HIV-1 during sexual transmission. LCs capture HIV-1 through the C-type lectin receptor langerin, which routes the virus into Birbeck granules (BGs), thereby preventing HIV-1 infection. BGs are langerin-positive organelles exclusively present in LCs, however, their origin and function are unknown.
  
  
  RESULTS
  Here, we not only show that langerin and caveolin-1 co-localize at the cell membrane and in vesicles but also that BGs are langerin/caveolin-1-positive vesicles are linked to the lysosomal degradation pathway in LCs. Moreover, inhibition of caveolar endocytosis in primary LCs abrogated HIV-1 sequestering into langerin(+) caveolar structures. Notably, both inhibition of caveolar uptake and silencing of caveolar structure protein caveolin-1 resulted in increased HIV-1 integration and subsequent infection. In contrast, inhibition of clathrin-mediated endocytosis did not affect HIV-1 integration, even though HIV-1 uptake was decreased, suggesting that clathrin-mediated endocytosis is not involved in HIV-1 restriction in LCs.
  
  
  CONCLUSIONS
  Thus, our data strongly indicate that BGs belong to the caveolar endocytosis pathway and that caveolin-1 mediated HIV-1 uptake is an intrinsic restriction mechanism present in human LCs that prevents HIV-1 infection. Harnessing this particular internalization pathway has the potential to facilitate strategies to combat HIV-1 transmission.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. l.m.vandenberg@amc.uva.nl.
authors.forename: Linda M
authors.initials: LM
authors.lastname: van den Berg
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. c.m.ribeiro@amc.uva.nl.
authors.forename: Carla M S
authors.initials: CM
authors.lastname: Ribeiro
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. e.m.zijlstra-willems@amc.uva.nl.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Zijlstra-Willems
authors.affiliation: Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands. l.d.deWitte@umcutrecht.nl.
authors.forename: Lot
authors.initials: L
authors.lastname: de Witte
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. dmfluitsma@gmail.com.
authors.forename: Donna
authors.initials: D
authors.lastname: Fluitsma
authors.affiliation: Department of Cell Biology & Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. w.tigchelaar@amc.uva.nl.
authors.forename: Wikky
authors.initials: W
authors.lastname: Tigchelaar
authors.affiliation: Department of Cell Biology & Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. v.everts@acta.nl.|Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam, University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands. v.everts@acta.nl.
authors.forename: Vincent
authors.initials: V
authors.lastname: Everts
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. t.b.geijtenbeek@amc.uva.nl.
authors.forename: Teunis B H
authors.initials: TB
authors.lastname: Geijtenbeek
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000821:virology; D004705:Endocytosis; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007801:Langerhans Cells / Q000821:virology*; D037181:Lectins, C-Type / Q000378:metabolism*; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D015703:Antigens, CD; C121916:CD207 protein, human; D051242:Caveolin 1; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins