Some viruses, such as HIV-1, appear to target lipid raft microdomains during viral entry into cells, as well as during viral assembly before budding from cells ( Dimitrov, 1997 Mañes et al., 2000). These microdomains, also known as lipid rafts, are localized regions with elevated cholesterol and glycosphingolipid content that can be found on the plasma- and endosomal-membrane of eukaryotic cells ( London and Brown, 2000 Simons and Toomre, 2000 Simons and Ehehalt, 2002). Recent works have demonstrated that some microbial pathogens exploit cholesterol-enriched lipid microdomains as essential docking sites to enter host cells ( Gatfield and Pieters, 2000 Rosenberger et al., 2000 Lafont et al., 2002). Recently, DC-SIGN was also shown to bind other viruses like CMV ( Halary et al., 2002), Ebola ( Alvarez et al., 2002), Dengue ( Tassaneetrithep et al., 2003), and hepatitis C ( Lozach et al., 2003 Pöhlmann et al., 2003), as well as microorganisms such as Leishmania ( Colmenares et al., 2002), Candida albicans ( Cambi et al., 2003), Mycobacterium ( Geijtenbeek et al., 2003 Maeda et al., 2003 Tailleux et al., 2003), and Schistosoma ( van Die et al., 2003). As a pathogen-recognition receptor, DC-SIGN binds HIV gp120 thus facilitating the transport of HIV from mucosal sites to draining lymph nodes where infection of T lymphocytes occurs ( Geijtenbeek et al., 2000b). As an adhesion receptor, DC-SIGN supports initial DC–T cell interaction by binding to ICAM-3 ( Geijtenbeek et al., 2000a), and mediates tethering and rolling of DCs on the endothelium by interacting with ICAM-2 ( Geijtenbeek et al., 2000c). Although some of them are members of the toll-like receptor (TLR) family, signaling molecules specialized in sensing pathogens ( Akira, 2003), others belong to the C-type lectin family and mediate pathogen binding and uptake ( Stahl and Ezekowitz, 1998 Mahnke et al., 2000).ĭC-specific intercellular adhesion molecule (ICAM) grabbing non-integrin (DC-SIGN CD209) is a C-type lectin specifically expressed by DCs and has a dual function. DCs are equipped with a variety of dynamically regulated pathogen-recognition receptors.
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Many C-type lectins act as cell adhesion receptors ( Vestweber and Blanks, 1999), whereas others are specialized in antigen recognition ( Stahl and Ezekowitz, 1998 Mahnke et al., 2000).ĭendritic cells (DCs) constitute a specific group of professional antigen presenting leukocytes, constantly patrolling the body for foreign intruders ( Steinman 1991 Banchereau and Steinman, 1998). Many of these lectins are members of the calcium-dependent C-type lectin family and recognize their ligands through the structurally related Ca 2+-dependent carbohydrate-recognition domains (C-type CRDs Drickamer, 1999). In the past two years, several new genes have been identified encoding leukocyte-specific carbohydrate binding proteins that belong to the lectin-like receptors family ( Kogelberg and Feizi, 2001 Figdor et al., 2002). Finally, we show that the organization of DC-SIGN in microdomains on the plasma membrane is important for binding and internalization of virus particles, suggesting that these multimolecular assemblies of DC-SIGN act as a docking site for pathogens like HIV-1 to invade the host.
Biochemical experiments and confocal microscopy indicate that DC-SIGN microdomains reside within lipid rafts. During development of human monocyte-derived DCs, DC-SIGN becomes organized in well-defined microdomains, with an average diameter of 200 nm. By high resolution electron microscopy, we demonstrate a direct relation between DC-SIGN function as viral receptor and its microlocalization on the plasma membrane. The C-type lectin dendritic cell (DC)–specific intercellular adhesion molecule grabbing non-integrin (DC-SIGN CD209) facilitates binding and internalization of several viruses, including HIV-1, on DCs, but the underlying mechanism for being such an efficient phagocytic pathogen-recognition receptor is poorly understood.
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