The most prevalent route of HIV-1 infection is across mucosal tissues after sexual contact. Langerhans cells (LCs) belong to the subset of dendritic cells (DCs) that line the mucosal epithelia of vagina and foreskin and have the ability to sense and induce immunity to invading pathogens1. Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection2. Notably, LCs form a protective barrier against HIV-1 infection and transmission3,4,5. LCs restrict HIV-1 infection through the capture of HIV-1 by the C-type lectin receptor Langerin and subsequent internalization into Birbeck granules5. However, the underlying molecular mechanism of HIV-1 restriction in LCs remains unknown. Here we show that human E3-ubiquitin ligase tri-partite-containing motif 5α (TRIM5α) potently restricts HIV-1 infection of LCs but not of subepithelial DC-SIGN+ DCs. HIV-1 restriction by TRIM5α was thus far considered to be reserved to non-human primate TRIM5α orthologues6,7,8,9, but our data strongly suggest that human TRIM5α is a cell-specific restriction factor dependent on C-type lectin receptor function. Our findings highlight the importance of HIV-1 binding to Langerin for the routeing of HIV-1 into the human TRIM5α-mediated restriction pathway. TRIM5α mediates the assembly of an autophagy-activating scaffold to Langerin, which targets HIV-1 for autophagic degradation and prevents infection of LCs. By contrast, HIV-1 binding to DC-SIGN+ DCs leads to disassociation of TRIM5α from DC-SIGN, which abrogates TRIM5α restriction. Thus, our data strongly suggest that restriction by human TRIM5α is controlled by C-type-lectin-receptor-dependent uptake of HIV-1, dictating protection or infection of human DC subsets. Therapeutic interventions that incorporate C-type lectin receptors and autophagy-targeting strategies could thus provide cell-mediated resistance to HIV-1 in humans.
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We are grateful to the members of the Host Defense group and Laboratory for Viral Immune Pathogenesis (Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands) for their input and D. Picavet (van Leeuwenhoek Centrum for Advanced Microscopy, Academic Medical Center, Amsterdam, The Netherlands) for technical assistance during confocal experiments. We wish to thank the Boerhaave Medical Centre (Amsterdam, The Netherlands) and A. Knottenbelt (Flevoclinic, Almere, The Netherlands) for the provision of human skin tissues. This work was supported by the Dutch Scientific Organization NWO (VENI 863.13.025 and VICI 918.10.619), Aids Fonds (2010038) and European Research Council (Advanced grant 670424).
Extended data figures
Extended data tables
DESCRIPThis file contains Supplementary Figure 1, gel source data with size marker indications for Figure 2a; Figure 3e,g,o; Figure 4e,i; Extended Data Fig. 2h-k, Extended Data Fig. 4a,b, Extended Data Fig. 5a,b and Extended Data Fig. 6a,c,d. It also contains Supplementary Table 1, primary data of HIV-1 integration Alu-PCR assay and calculation of relative HIV-1 integration; see also Figure 1a.TION
About this article
Nature Reviews Microbiology (2018)