Receptor usage dictates HIV-1 restriction by human TRIM5α in dendritic cell subsets

Abstract

Human TRIM5α restricts HIV-1 infection of Langerhans cells through Langerin-dependent autophagy pathway. Teunis Geijtenbeek and colleagues find a role for human E3-ubiquitin ligase tri-partite-containing motif 5α (TRIM5α) in restricting HIV-1 infection in Langerhans cells, a subset of dendritic cells present at the mucosal barrier. They show that capture of HIV-1 by the C-type lectin receptor Langerin serves to route the virus to a TRIM5α- and Langerin-dependent autophagy pathway. This mechanism of TRIM5α-mediated restriction differs from the proteasome-dependent mechanism by which rhesus TRIM5α is thought to restrict HIV-1, and seems to be a Langerhans-cell-specific restriction mechanism operating at the mucosal barrier. Langerhans cells are important in the defence against HIV-1 infection during sexual transmission, and this work highlights the potential of interventions involving C-type lectin receptors and autophagy-targeting strategies to promote cell-mediated resistance to HIV-1. 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.

Cite this article

Ribeiro, C., Sarrami-Forooshani, R., Setiawan, L. et al. Receptor usage dictates HIV-1 restriction by human TRIM5α in dendritic cell subsets. Nature 540, 448–452 (2016). https://doi.org/10.1038/nature20567

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