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

Abstract

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 pathogens. Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection. Notably, LCs form a protective barrier against HIV-1 infection and transmission. LCs restrict HIV-1 infection through the capture of HIV-1 by the C-type lectin receptor Langerin and subsequent internalization into Birbeck granules. 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 orthologues, 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.

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

“…This observation is consistent with previous studies showing that innate responses in the mucosa immediately following infection are inducing a potent antiviral state through the up-regulation of ISGs, many of which have anti-HIV-1 activity (63,64,(66)(67)(68)(69)(70)(71)(72)(73). All IFN subtypes signal through the same heterodimeric receptor (30), but differences in receptor binding and/or downstream signal transduction pathways are thought to be responsible for IFN subtype-specific biological effects (74)(75)(76)(77).…”

Ebola virus infection kinetics in chimeric mice reveal a key role of T cells as barriers for virus dissemination

“…Interestingly, one of the main migratory DC subsets, the CD103 + DCs does not seem to play a role on EBOV dissemination since we did not detect expression of viral GP in the surface of CD103 + DCs. Interestingly, there are substantial parallelisms between our study and a recent HIV report which indicated that productive infection of DC-SIGN + but not langerin + DCs by HIV depended on the C-type lectin receptor usage25. Since CD103 + DCs express langerin26 but not DC-SIGN, it seems worthwhile to determine whether EBOV can actually infect CD103 + DCs or rather whether the virus cannot replicate in these cells.…”

Autophagy and Viral Infection

“…In Langerhans cells, which are dendritic immune skin cells, HIV was degraded by the restriction factor tripartite motif-containing protein 5α (TRIM5α) and its ability to regulate the assembly of autophagy activating complexes ( Fig. 5.4) [110].…”