Gringhuis, SI, van der Vlist, M, van den Berg, LM, den Dunnen, J, Litjens, M and Geijtenbeek, TB. HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells. Nat Immunol 11: 419-426

Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Nature Immunology (Impact Factor: 20). 04/2010; 11(5):419-26. DOI: 10.1038/ni.1858
Source: PubMed


Pattern-recognition receptors (PRRs) elicit antiviral immune responses to human immunodeficiency virus type 1 (HIV-1). Here we show that HIV-1 required signaling by the PRRs Toll-like receptor 8 (TLR8) and DC-SIGN for replication in dendritic cells (DCs). HIV-1 activated the transcription factor NF-kappaB through TLR8 to initiate the transcription of integrated provirus by RNA polymerase II (RNAPII). However, DC-SIGN signaling was required for the generation of full-length viral transcripts. Binding of the HIV-1 envelope glycoprotein gp120 to DC-SIGN induced kinase Raf-1-dependent phosphorylation of the NF-kappaB subunit p65 at Ser276, which recruited the transcription-elongation factor pTEF-b to nascent transcripts. Transcription elongation and generation of full-length viral transcripts was dependent on pTEF-b-mediated phosphorylation of RNAPII at Ser2. Inhibition of either pathway abrogated replication and prevented HIV-1 transmission. Thus, HIV-1 subverts crucial components of the immune system for replication that might be targeted to prevent infection and dissemination.

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Available from: Michiel van der Vlist
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    • "Similarly, during evolution and selection , the tetramer and matching CRD structure of DC-SIGN maybe optimally contribute multiple binding positions on one tetrameric molecule for HIV-1 virions. Engagement of HIV-1 Env to DC-SIGN or DCIR can induce phosphorylation of corresponding CLR in its cytoplasmic tail, consequently activating a signal transduction pathway that contributes to HIV-1 immune evasion, productive proliferation and infection (Gringhuis et al., 2010; Lambert et al., 2011; Sarkar et al., 2013). For instance, activation of DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication (Hodges et al., 2007). "
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    ABSTRACT: The C-type lectin receptors (CLRs) expressed on dendritic cells (DCs), in particular DC-SIGN and DCIR, likely play an important role in HIV-1 early infection. Here, we systematically compared the capture and transfer capability of DC-SIGN and DCIR using a wide range of HIV-1 isolates. Our results indicated that DC-SIGN plays a stronger role than DCIR in DC-mediated HIV-1 capture and transfer. This was further strengthened by the data from transient and stable transfectants, showing that DC-SIGN had better capability, compared with DCIR in HIV-1 capture and transfer. Following constructing and analyzing a series of soluble DC-SIGN and DCIR truncates and chimeras, we demonstrated that the neck domain, but not the CRD, renders DC-SIGN higher binding affinity to gp120 likely via the formation of tetramerization. Our findings provide insights into CLR-mediated HIV-1 capture and transfer, highlighting potential targets for intervention strategies against gp120-CLR interactions.
    Full-text · Article · Jun 2014 · Virology
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    • "First, guanine-uridine-rich ssRNA derived from HIV is recognized by TLR7/8 and stimulates plasmacytoid DCs (pDC)s and macrophages to secrete IFNα and pro-inflammatory cytokines [41], [42], and also increases cytotoxicity and IFNγ production from natural killer cells [43]. Moreover, interaction between HIV gp120 and DC-SIGN induces phosphorylation of NF-κB, and this signal from DC-SIGN appears to be required for elongation of viral transcripts and hence for synthesis of complete transcripts and productive infection [44]. Within the cytoplasm, RIG-I has been proposed to recognize HIV genomic ssRNA [45], [46]. "
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    ABSTRACT: HIV infects key cell types of the immune system, most notably macrophages and CD4+ T cells. Whereas macrophages represent an important viral reservoir, activated CD4+ T cells are the most permissive cell types supporting high levels of viral replication. In recent years, it has been appreciated that the innate immune system plays an important role in controlling HIV replication, e.g. via interferon (IFN)-inducible restriction factors. Moreover, innate immune responses are involved in driving chronic immune activation and the pathogenesis of progressive immunodeficiency. Several pattern recognition receptors detecting HIV have been reported, including Toll-like receptor 7 and Retinoic-inducible gene-I, which detects viral RNA. Here we report that human primary T cells fail to induce strong IFN responses, despite the fact that this cell type does express key molecules involved in DNA signaling pathways. We demonstrate that the DNA sensor IFI16 migrates to sites of foreign DNA localization in the cytoplasm and recruits the signaling molecules stimulator of IFN genes and Tank-binding kinase, but this does not result in expression of IFN and IFN-stimulated genes. Importantly, we show that cytosolic DNA fails to affect HIV replication. However, exogenous treatment of activated T cells with type I IFN has the capacity to induce expression of IFN-stimulated genes and suppress HIV replication. Our data suggest the existence of an impaired DNA signaling machinery in T cells, which may prevent this cell type from activating cell-autonomous anti-HIV responses. This phenomenon could contribute to the high permissiveness of CD4+ T cells for HIV-1.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "We previously reported that Syk is important for an efficient HIV-1 infection of iDCs and subsequent virus transfer to CD4+ T cells [48]. Given that dectin-1 and DC-SIGN interact together to mediate signal transduction events in DCs [49], that zymosan can engage both dectin-1 and DC-SIGN, and that HIV-1 infection of DCs is promoted by an interaction between virus-associated gp120 and DC-SIGN [44], it can be proposed that the zymosan-directed enhancement in virus replication in DCs is due to both dectin-1 and DC-SIGN. Similarly, the activation of NOD2 also leads to inflammasome activation. "
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    ABSTRACT: HIV-1 pathogenesis is intimately linked with microbial infections and innate immunity during all stages of the disease. While the impact of microbial-derived products in transmission of R5-using virus to CD4(+) T cells by dendritic cells (DCs) has been addressed before, very limited data are available on the effect of such compounds on DC-mediated dissemination of X4-tropic variant. Here, we provide evidence that treatment of DCs with dectin-1/TLR2 and NOD2 ligands increases cis-infection of autologous CD4(+) T cells by X4-using virus. This phenomenon is most likely associated with an enhanced permissiveness of DCs to productive infection with X4 virus, which is linked to increased surface expression of CXCR4 and the acquisition of a maturation profile by DCs. The ensuing DC maturation enhances susceptibility of CD4(+) T cells to productive infection with HIV-1. This study highlights the crucial role of DCs at different stages of HIV-1 infection and particularly in spreading of viral strains displaying a X4 phenotype.
    Preview · Article · Jul 2013 · PLoS ONE
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