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Pohlmann, S. et al. DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proc. Natl Acad. Sci. USA 98, 2670-2675

Department of Pathology and Laboratory Medicine, University of Pennsylvania, 806 Abramson, Philadelphia, PA 19104, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2001; 98(5):2670-5. DOI: 10.1073/pnas.051631398
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ABSTRACT DC-SIGN, a C-type lectin expressed on the surface of dendritic cells (DCs), efficiently binds and transmits HIVs and simian immunodeficiency viruses to susceptible cells in trans. A DC-SIGN homologue, termed DC-SIGNR, has recently been described. Herein we show that DC-SIGNR, like DC-SIGN, can bind to multiple strains of HIV-1, HIV-2, and simian immunodeficiency virus and transmit these viruses to both T cell lines and human peripheral blood mononuclear cells. Binding of virus to DC-SIGNR was dependent on carbohydrate recognition. Immunostaining with a DC-SIGNR-specific antiserum showed that DC-SIGNR was expressed on sinusoidal endothelial cells in the liver and on endothelial cells in lymph node sinuses and placental villi. The presence of this efficient virus attachment factor on multiple endothelial cell types indicates that DC-SIGNR could play a role in the vertical transmission of primate lentiviruses, in the enabling of HIV to traverse the capillary endothelium in some organs, and in the presentation of virus to CD4-positive cells in multiple locations including lymph nodes.

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    • "Although it was originally marketed as specific for CD209, the DCN46 antibody has recently been shown to cross-react with CD299/L-SIGN/CLEC4M [13], a molecule previously reported to be expressed by sinusoidal endothelial cells in human LNs and liver [14], [15]. To confirm which of the DCN46+ cells in the sinuses were CD209+, we used a second antibody to CD209 (Figure 5A–D, Figure S4 in File S1). "
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    ABSTRACT: The lymphatic sinuses in human lymph nodes (LNs) are crucial to LN function yet their structure remains poorly defined. Much of our current knowledge of lymphatic sinuses derives from rodent models, however human LNs differ substantially in their sinus structure, most notably due to the presence of trabeculae and trabecular lymphatic sinuses that rodent LNs lack. Lymphatic sinuses are bounded and traversed by lymphatic endothelial cells (LECs). A better understanding of LECs in human LNs is likely to improve our understanding of the regulation of cell trafficking within LNs, now an important therapeutic target, as well as disease processes that involve lymphatic sinuses. We therefore sought to map all the LECs within human LNs using multicolor immunofluorescence microscopy to visualize the distribution of a range of putative markers. PROX1 was the only marker that uniquely identified the LECs lining and traversing all the sinuses in human LNs. In contrast, LYVE1 and STAB2 were only expressed by LECs in the paracortical and medullary sinuses in the vast majority of LNs studied, whilst the subcapsular and trabecular sinuses lacked these molecules. These data highlight the existence of at least two distinctive populations of LECs within human LNs. Of the other LEC markers, we confirmed VEGFR3 was not specific for LECs, and CD144 and CD31 stained both LECs and blood vascular endothelial cells (BECs); in contrast, CD59 and CD105 stained BECs but not LECs. We also showed that antigen-presenting cells (APCs) in the sinuses could be clearly distinguished from LECs by their expression of CD169, and their lack of expression of PROX1 and STAB2, or endothelial markers such as CD144. However, both LECs and sinus APCs were stained with DCN46, an antibody commonly used to detect CD209.
    PLoS ONE 04/2014; 9(4):e94781. DOI:10.1371/journal.pone.0094781 · 3.23 Impact Factor
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    • "In addition to DC-SIGN being used as a receptor, a number of pathogens including West Nile virus and ebola virus use the closely related DC-SIGNR (CD209R) protein as a receptor for infection [40], [41]. DC-SIGNR shares a 73% sequence identity on the nucleotide level with DC-SIGN, but unlike DC-SIGN is found on lymph node and liver sinusoidal endothelial cells [42], [43], [44], [45]. Due to its localization, it is thought that DC-SIGNR may have a role in peripheral tolerance, but its exact role in pathogen responses has not been well characterized. "
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    ABSTRACT: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of multicentric Castleman's disease, primary effusion lymphoma and Kaposi's sarcoma. In this study, we show that like the C-type lectin DC-SIGN, the closely related DC-SIGNR can also enhance KSHV infection. Following infection, they are both targeted for down modulation and our data indicate that the KSHV MARCH-family ubiquitin ligase K5 is mediating this regulation and subsequent targeting for degradation of DC-SIGN and DC-SIGNR in the context of the virus. The closely related viral K3 protein, is also able to target these lectins in exogenous expressions studies, but only weakly during viral infection. In addition to requiring a functional RING-CH domain, several protein trafficking motifs in the C-terminal region of both K3 and K5 are important in regulation of DC-SIGN and DC-SIGNR. Further exploration of this modulation revealed that DC-SIGN is endocytosed from the cell surface in THP-1 monocytes, but degraded from an internal location with minimal endocytosis in HEK-293 cells. Pull-down data indicate that both K3 and K5 preferentially associate with immature forms of the lectins, mediating their ubiquitylation and degradation. Together, these data emphasize the molecular complexities of K3 and K5, while expanding the repertoire of targets of these two viral proteins.
    PLoS ONE 02/2013; 8(2):e58056. DOI:10.1371/journal.pone.0058056 · 3.23 Impact Factor
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    • "Since mature DCs potently resist HIV-1 infection by various mechanisms, including the high expression of the recently identified restriction factor SamHD1, only a small proportion of DCs is productively infected [31-33]. Instead, they capture the virus via cell surface lectins such as DC-SIGN and home into lymph nodes or other secondary lymphatic organs, where they transmit surface bound HIV-1 to CD4+ T cells [32,34,35]. "
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