Affiliation: | 1.Department of Experimental Immunology, Academic Medical Center,University of Amsterdam,Amsterdam,The Netherlands;2.Department of Psychiatry,University Medical Center Utrecht,Utrecht,The Netherlands;3.Department of Molecular Cell Biology and Immunology,VU University Medical Center,Amsterdam,The Netherlands;4.Department of Cell Biology & Histology, Academic Medical Center,University of Amsterdam,Amsterdam,The Netherlands;5.Department of Oral Cell Biology, Academic Center for Dentistry Amsterdam,University of Amsterdam and VU University Amsterdam,Amsterdam,The Netherlands |
Abstract: | BackgroundHuman 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.ResultsHere, 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.ConclusionsThus, 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. |