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Gringhuis, Geijtenbeek and colleagues show that the RNA helicase DDX3 binds abortive HIV-1 RNA and induces type I interferon in dendritic cells, a process that is inhibited by the HIV-1-induced activation of kinase PLK1. The mechanisms by which human immunodeficiency virus 1 (HIV-1) avoids immune surveillance by dendritic cells (DCs), and thereby prevents protective adaptive immune responses, remain poorly understood. Here we showed that HIV-1 actively arrested antiviral immune responses by DCs, which contributed to efficient HIV-1 replication in infected individuals. We identified the RNA helicase DDX3 as an HIV-1 sensor that bound abortive HIV-1 RNA after HIV-1 infection and induced DC maturation and type I interferon responses via the signaling adaptor MAVS. Notably, HIV-1 recognition by the C-type lectin receptor DC-SIGN activated the mitotic kinase PLK1, which suppressed signaling downstream of MAVS, thereby interfering with intrinsic host defense during HIV-1 infection. Finally, we showed that PLK1-mediated suppression of DDX3–MAVS signaling was a viral strategy that accelerated HIV-1 replication in infected individuals.

Vaginal inflammation increases the risk for sexual HIV-1 transmission but underlying mechanisms remain unclear. In this study we assessed the impact of immune activation on HIV-1 susceptibility of primary human vaginal Langerhans cells (LCs). Vaginal LCs isolated from human vaginal tissue expressed a broad range of TLRs and became activated after exposure to both viral and bacterial TLR ligands. HIV-1 replication was restricted in immature vaginal LCs as only low levels of infection could be detected. Notably, activation of immature vaginal LCs by bacterial TLR ligands increased HIV-1 infection, whereas viral TLR ligands were unable to induce HIV-1 replication in vaginal LCs. Furthermore, mature vaginal LCs transmitted HIV-1 to CD4 T cells. This study emphasizes the role for vaginal LCs in protection against mucosal HIV-1 infection, which is abrogated upon activation. Moreover, our data suggest that bacterial STIs can increase the risk of HIV-1 acquisition in women.

Strong innate and adaptive immune responses are paramount in combating viral infections. Dendritic cells (DCs) detect viral infections via cytosolic RIG-I like receptors (RLRs) RIG-I and MDA5 leading to MAVS-induced immunity. The DEAD-box RNA helicase DDX3 senses abortive human immunodeficiency virus 1 (HIV-1) transcripts and induces MAVS-dependent type I interferon (IFN) responses, suggesting that abortive HIV-1 RNA transcripts induce antiviral immunity. Little is known about the induction of antiviral immunity by DDX3-ligand abortive HIV-1 RNA. Here we synthesized a 58 nucleotide-long capped RNA (HIV-1 Cap-RNA ) that mimics abortive HIV-1 RNA transcripts. HIV-1 Cap-RNA induced potent type I IFN responses in monocyte-derived DCs, monocytes, macrophages and primary CD1c DCs. Compared with RLR agonist poly-I:C, HIV-1 Cap-RNA induced comparable levels of type I IFN responses, identifying HIV-1 Cap-RNA as a potent trigger of antiviral immunity. In monocyte-derived DCs, HIV-1 Cap-RNA activated the transcription factors IRF3 and NF-κB. Moreover, HIV-1 Cap-RNA induced DC maturation and the expression of pro-inflammatory cytokines. HIV-1 Cap-RNA -stimulated DCs induced proliferation of CD4 and CD8 T cells and differentiated naïve T helper (T ) cells toward a T 2 phenotype. Importantly, treatment of DCs with HIV-1 Cap-RNA resulted in an efficient antiviral innate immune response that reduced ongoing HIV-1 replication in DCs. Our data strongly suggest that HIV-1 Cap-RNA induces potent innate and adaptive immune responses, making it an interesting addition in vaccine design strategies.

BackgroundHouse dust mite (HDM) is a major cause of respiratory allergic diseases. Dendritic cells (DCs) play a central role in orchestrating adaptive allergic immune responses. However, it remains unclear how DCs become activated by HDM. Biochemical functions of the major HDM allergens Der p 1 (cysteine protease) and Der p 2 (MD2-mimick) have been implicated to contribute to DC activation.MethodsWe investigated the immune activating potential of HDM extract and its major allergens Der p 1 and Der p 2 using monocyte-derived DCs (moDCs). Maturation and activation markers were monitored by flow cytometry and cytokine production by ELISA. Allergen depletion and proteinase K digestion were used to investigate the involvement of proteins, and in particular of the major allergens. Inhibitors of spleen tyrosine kinase (Syk), Toll-like receptor 4 (TLR4) and of C-type lectin receptors (CLRs) were used to identify the involved receptors. The contribution of endotoxins in moDC activation was assessed by their removal from HDM extract.ResultsHDM extract induced DC maturation and cytokine responses in contrast to the natural purified major allergens Der p 1 and Der p 2. Proteinase K digestion and removal of Der p 1 or Der p 2 did not alter the immune stimulatory capacity of HDM extract. Antibodies against the CLRs Dectin-1, Dectin-2, and DC-SIGN did not affect cytokine responses. In contrast, Syk inhibition partially reduced IL-6, IL-12 and completely blocked IL-10. Blocking TLR4 signaling reduced the HDM-induced IL-10 and IL-12p70 induction, but not IL-6, while endotoxin removal potently abolished the induced cytokine response.ConclusionOur data strongly suggest that HDM-induced DC activation is neither dependent on Der p 1 nor Der p 2, but depend on Syk and TLR4 activation, which might suggest a crosstalk between Syk and TLR4 pathways. Our data highlight that endotoxins play a potent role in immune responses targeting HDM.

Human TRIM5α restricts HIV-1 infection of Langerhans cells through Langerin-dependent autophagy pathway. C-type lectin receptor-mediated anti-HIV activity 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 pathogens 1 . Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection 2 . Notably, LCs form a protective barrier against HIV-1 infection and transmission 3 , 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 granules 5 . 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 6 , 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.

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.

Human TRIM5[alpha] restricts HIV-1 infection of Langerhans cells through Langerin-dependent autophagy pathway. C-type lectin receptor-mediated anti-HIV activity Teunis Geijtenbeek and colleagues find a role for human E3-ubiquitin ligase tri-partite-containing motif 5[alpha] (TRIM5[alpha]) 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 TRIM5[alpha]- and Langerin-dependent autophagy pathway. This mechanism of TRIM5[alpha]-mediated restriction differs from the proteasome-dependent mechanism by which rhesus TRIM5[alpha] 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 pathogens.sup.1. Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection.sup.2. Notably, LCs form a protective barrier against HIV-1 infection and transmission.sup.3,4,5. LCs restrict HIV-1 infection through the capture of HIV-1 by the C-type lectin receptor Langerin and subsequent internalization into Birbeck granules.sup.5. 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 5[alpha] (TRIM5[alpha]) potently restricts HIV-1 infection of LCs but not of subepithelial DC-SIGN.sup.+ DCs. HIV-1 restriction by TRIM5[alpha] was thus far considered to be reserved to non-human primate TRIM5[alpha] orthologues.sup.6,7,8,9, but our data strongly suggest that human TRIM5[alpha] 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 TRIM5[alpha]-mediated restriction pathway. TRIM5[alpha] 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.sup.+ DCs leads to disassociation of TRIM5[alpha] from DC-SIGN, which abrogates TRIM5[alpha] restriction. Thus, our data strongly suggest that restriction by human TRIM5[alpha] 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.

Human TRIM5[alpha] restricts HIV-1 infection of Langerhans cells through Langerin-dependent autophagy pathway.

Nat. Immunol. 18, 225–235 (2017); published online 26 December 2016; corrected after print 23 January 2017 In the version of this article initially published, the fifth author's surname was spelled incorrectly (as 'Sarrami-Fooroshani'). The correct spelling is 'Sarrami-Forooshani'. Also, the cells for the third plot in Figure 1d were identified incorrectly as 'Intesrinal DCs'.

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 5a (TRIM5a) potently restricts HIV-1 infection of LCs but not of subepithelial DC-SIGN+ DCs. HIV-1 restriction by TRIM5a was thus far considered to be reserved to non-human primate TRIM5a orthologues, but our data strongly suggest that human TRIM5a 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 TRIM5amediated restriction pathway. TRIM5a 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 TRIM5a from DC-SIGN, which abrogates TRIM5a restriction. Thus, our data strongly suggest that restriction by human TRIM5a 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.