Abstract
Footnotes
†Present address: GlaxoSmithKline R&D, B38 2 58, Greenford Road, London UB6 0HE, UK.Approximately 170 million people worldwide are persistently infected with the Hepatitis C virus (HCV) (Cooper et al., 1999; Lechner et al., 2000). These individuals may remain asymptomatic or they may develop chronic hepatitis or cirrhosis, the latter often leading to hepatocellular carcinoma (Fry & Flint, 1997). Hepatocytes are the major target cells of HCV (Boisvert et al., 2001; Fournier et al., 1998; Ikeda et al., 1998) and the tissue tropism of the virus is restricted by the envelope glycoproteins E1 and E2 (E1E2) (Lavillette et al., 2005; McKeating et al., 2004). E1 has homologies to the class II fusion proteins of other flaviviruses and alphaviruses (Garry & Dash, 2003). E2 is a receptor-binding subunit with affinity for CD81 (Pileri et al., 1998), which serves as an entry co-receptor for HCV (Cormier et al., 2004b; McKeating et al., 2004) and additional molecules implicated in HCV entry (Bartosch et al., 2003; Lavillette et al., 2005; Scarselli et al., 2002). We and others have demonstrated that L-SIGN (liver/lymph node-specific, intercellular adhesion molecule-3-grabbing non-integrin, CD209L or DC-SIGNR) also binds soluble HCV E2 (sE2) and mediates trans-infection of liver cells by HCV pseudoparticles (HCVpp) (Cormier et al., 2004a; Gardner et al., 2003; Lozach et al., 2003, 2004; Pohlmann et al., 2003). L-SIGN may concentrate HCV in the liver and enable captured virus to cross the endothelial barrier, thereby facilitating infection of adjacent hepatocytes.
L-SIGN and DC-SIGN (dendritic cell-specific, CD209) are homologous type II membrane proteins characterized by a carboxyl-terminal carbohydrate-recognition domain (CRD), a juxtamembrane oligomerization or neck domain, a single transmembrane-spanning domain and a short cytoplasmic tail. L-SIGN is expressed on liver sinusoidal endothelial cells (Bashirova et al., 2001; Pohlmann et al., 2001b; Soilleux et al., 2000), which are specialized non-myeloid antigen-presenting cells involved in immune surveillance (Knolle & Gerken, 2000). DC-SIGN is important for activation of resting T cells (Geijtenbeek et al., 2000a). In addition, the SIGN molecules act as receptors for certain viral and non-viral pathogens by binding high-mannose and related surface glycans. For Human immunodeficiency virus 1 (HIV-1), the SIGN molecules do not act as conventional entry receptors. Instead, SIGN-expressing cells capture virus and facilitate its delivery to, and trans-infection of, susceptible target cells (Geijtenbeek et al., 2000b; Pohlmann et al., 2001a, b).
L-SIGN gene polymorphisms have been identified that differ in the number of repeats of a 69 bp sequence in the neck region (Bashirova et al., 2001; Feinberg et al., 2005; Liu & Zhu, 2005). Each repeat encodes a hydrophobic heptad motif characteristic of α-helical coiled coils (Feinberg et al., 2005; Mitchell et al., 2001). In Caucasians, the most common L-SIGN allele encodes seven repeat segments (L-SIGN-7) and comprises just over 50 % of all alleles. Other alleles encode from three to nine tandem repeats (L-SIGN-3 to L-SIGN-9) and vary in frequency from 0.3 (L-SIGN-3) to 29 % (L-SIGN-5) (Bashirova et al., 2001). Little is known about the expression and function of these L-SIGN isoforms at the cell surface. Fig. 1 depicts the domain structures of the proteins encoded by the L-SIGN isoforms examined in this study. The 23 aa repeat segments are numbered relative to those encoded by L-SIGN-7, with the first repeat beginning at Ile-89 (Mummidi et al., 2001).
|
DNA encoding L-SIGN-7 and HeLa cells expressing this allele have been described previously by us (Cormier et al., 2004a; Gardner et al., 2003). DNAs encoding the 3-, 4-, 5- and 9-repeat forms of L-SIGN were synthesized chemically (DNA 2.0) and subcloned into the pcDNA3.1 expression vector (Invitrogen). HeLa cells were modified to express L-SIGN isoforms stably and analysed by flow cytometry following staining with monoclonal antibodies (mAbs). Using mAb 120604 to the CRD (R&D Systems), each of the isoforms was detected at high levels, demonstrating that the proteins were expressed efficiently and transported to the cell surface (Fig. 2a). Similar results were obtained using another CRD-specific mAb (120612; R&D Systems), as well as mAb DC28 (R&D Systems) to the repeat region (data not shown). Expression of all alleles was calculated relative to L-SIGN-7 (Fig. 2b) and these expression ratios were used to normalize sE2 binding and trans-infection with HCVpp. Moreover, non-quantitative Western blots were performed with mAb DC28 to confirm that L-SIGN isoforms expressed in HeLa cells differed in size, as expected (Fig. 2c). When deglycosylated, each L-SIGN isoform migrated as one major band consistent with its expected molecular mass. Multiple major bands were observed in the absence of N-glycosidase F (PNGase F) treatment for most isoforms and suggest glycosylation variants. The molecular mass observed for untreated L-SIGN-7 was consistent with prior reports (Pohlmann et al., 2001b).
|
Previously, we showed that DC-SIGN and L-SIGN-7 specifically bind sE2 from a subtype 1a isolate, HCVpp coated with E1E2 of the H77 1a isolate and HCV virions from subtype 1a-infected individuals (Cormier et al., 2004a; Gardner et al., 2003). Here, we used a flow-cytometry method to examine binding of sE2 to L-SIGN isoforms, according to a protocol previously described by us (Gardner et al., 2003). Detection of sE2 capture by L-SIGN relied on anti-E2 mAb 091a-5 (Austral) coupled to FluoSpheres (Molecular Probes). This mAb does not detect sE2 bound to CD81; hence the low expression level of this viral receptor on HeLa cells did not interfere with our assay. The mean MFI observed for parental HeLa cells was 5±3, whereas levels of specific binding to L-SIGN transfectants were 9- to 25-fold above background binding. Moreover, binding of sE2 was normalized for L-SIGN isoform-expression ratios that were measured in parallel within each experiment. Soluble E2 glycoprotein bound all isoforms but with different efficiencies (Fig. 3a). The strongest binding was to L-SIGN-7, whereas the weakest binding was exhibited by isoform 3 and this difference was statistically significant (P=0.04). The differences observed between L-SIGN-7 and the other three isoforms followed a trend towards significance (0.1<P<0.2). All statistical analyses were performed using an unpaired t-test to calculate two-tailed P values.
|
To determine whether the pattern of sE2 binding to L-SIGN isoforms was recapitulated by the native envelope glycoprotein, we measured HCVpp binding to parental HeLa cells and cells expressing L-SIGN alleles 3 or 7 (chosen because they exhibited the most significant difference in the sE2 binding assay). Binding of HCVpp was quantified as described previously (Cormier et al., 2004a; Gardner et al., 2003). Briefly, cells were incubated with purified and concentrated HCVpp in a binding buffer and then washed extensively to remove unbound virus. Cell lysates were analysed for HIV-1 p24 content using the Coulter HIV-1 p24 antigen assay (Beckman Coulter). Background binding to parental HeLa cells was 546±98 ng ml1. In contrast, binding to L-SIGN-positive cells was significantly higher and also different between the two alleles. Mean p24 values from three independent experiments were 960±126 ng ml1 for HeLaL-SIGN-3 cells and 2006±159 ng ml1 for HeLaL-SIGN-7 cells (P=0.01). These differences remained significant even when normalized for expression levels of the two alleles (1247 versus 2006 ng ml1) (Fig. 3a, below x axis). Note that the input amount of HCVpp-associated p24 was 10 µg ml1, resulting in approximately 10 and 20 % capture efficiencies of pseudoparticles by HeLaL-SIGN-3 and -7 cells, respectively.
Parental HeLa cells and HeLa-SIGN transfectants then were analysed for their abilities to mediate trans-infection of Huh-7 hepatoma cells by HCVpp bearing the envelope glycoproteins of the H77 1a isolate, as described previously (Cormier et al., 2004a). Trans-infection levels were normalized for L-SIGN allele-expression levels and a pattern similar to the one observed for sE2 and HCVpp binding emerged (Fig. 3b). The highest levels of trans-infection were mediated by L-SIGN-7-expressing HeLa cells, followed by L-SIGN-9, -5, -4 and -3. The difference between the trans-infection efficiencies of L-SIGN-7 and L-SIGN-9 was not statistically significant (P=0.577). However, differences between L-SIGN-7 and the other isoforms were statistically significant: L-SIGN-3 (P=0.0001), L-SIGN-4 (P=0.002) and L-SIGN-5 (P=0.003).
In order to ascertain that trans-infection was mediated specifically by L-SIGN isoforms, it was also examined in the presence of >IC90 concentrations of agents that bind the CRD (Cormier et al., 2004a). Mannan (Sigma), as well as mAbs 120604 and 120612, efficiently blocked trans-infection mediated by each of the L-SIGN isoforms (Fig. 3b). The level of trans-infection was inhibited by 58100 % for mAb 120604, 68100 % for mAb 120602 and 4882 % for mannan. In contrast, isotype-control mouse IgG had no effect on trans-infection and was used as the positive control in Fig. 3(b). There was no obvious variation between the different isoforms in the potency of the inhibitors at the concentrations used. The data indicated that L-SIGN-3, -4, -5 and -9 mediated trans-infection via interactions between their CRD and HCVpp, as observed previously for L-SIGN-7 (Cormier et al., 2004a; Lozach et al., 2004).
This report evaluated the expression and function in mammalian cells of L-SIGN variants that comprised three, four, five, seven or nine oligomerization domain repeats. We demonstrated that alleles encoding the five isoforms were translated efficiently and correctly, were exported to the surface of HeLa cells and were reactive with mAbs to the CRD and repeat region. Each of these isoforms bound different levels of HCV sE2. The statistically significant difference observed between isoforms 3 and 7 was confirmed by their different efficiencies at capturing HCVpp. Capture differences translated into different trans-infection efficiencies of liver cells by HCVpp. Soluble E2 binding, HCVpp capture and trans-infection were highest for L-SIGN-7, decreased with progressive deletions of tandem repeats and were lowest for L-SIGN-3.
Variations in HCVpp capture and trans-infection could reflect differences in the oligomeric states of the L-SIGN isoforms and support for this notion is provided by recent studies. Cell-surface L-SIGN-7 and DC-SIGN exist as tetramers (Bernhard et al., 2004; Feinberg et al., 2005; Mitchell et al., 2001), as do recombinant, soluble forms of these proteins (Feinberg et al., 2005; Mitchell et al., 2001; Snyder et al., 2005). A recent study showed a gradual increase in the ability of L-SIGN isoforms with four, five, six or seven repeats to form stable tetramers (Guo et al., 2006). Moreover, soluble SIGN molecules containing one to two tandem repeats form monomers and dimers, whereas a five-repeat version of soluble DC-SIGN forms a mixture of dimers and tetramers (Feinberg et al., 2005; Snyder et al., 2005). It appears, therefore, that increasing the number of repeats increases the oligomerization state of SIGN receptors, which may affect their avidity for glycan ligands. In the context of soluble L-SIGN proteins, the number of tandem repeats has been reported to influence binding affinity for HIV-1 gp120 (Snyder et al., 2005).
Our findings may have implications for the transmission and pathogenesis of HCV. As proposed previously, L-SIGN may capture HCV in the liver and deliver virus to susceptible hepatocytes (Gardner et al., 2003; Lozach et al., 2003, 2004; Pohlmann et al., 2003). L-SIGN isoforms could influence the in vivo process by mediating trans-infection with varying efficiencies. Polymorphisms in L-SIGN and DC-SIGN could thereby afford protection against HCV infection and disease progression, and future studies will examine whether L-SIGN repeat-region gene polymorphisms are more prevalent in high-risk individuals who remain uninfected or in individuals who resolve disease. In addition, polymorphisms in L-SIGN and DC-SIGN could affect HCV disease by modulating host immune responses to the virus.
Similarly, direct infection and trans-infection by other pathogens may be affected by L-SIGN polymorphisms. L-SIGN and DC-SIGN bind to or facilitate infection by a diverse array of viral and non-viral pathogens, including HIV-1 and other primate lentiviruses (Baribaud et al., 2001; Geijtenbeek et al., 2000b; Lee et al., 2001), Ebola virus (Alvarez et al., 2002), Marburg virus (Marzi et al., 2004), Dengue virus (Tassaneetrithep et al., 2003), severe acute respiratory syndrome coronavirus (SARS-CoV) (Marzi et al., 2004; Yang et al., 2004), cytomegalovirus (Halary et al., 2002), Sindbis virus (Klimstra et al., 2003), Leishmania amastigotes (Colmenares et al., 2002), Mycobacterium tuberculosis (Geijtenbeek et al., 2003), Candida albicans (Cambi et al., 2003), Helicobacter pylori (Bergman et al., 2004) and Aspergillus fumigatus (Serrano-Gomez et al., 2004). We note, however, that a recent in vitro study by Gramberg et al. (2006) did not find a significant difference in cis-infection by SARS-CoV and Ebola or trans-infection of HIV-1 mediated by L-SIGN isoforms 5, 6 and 7. Moreover this group did not find major differences in the oligomerization states of the different isoforms. Other recent studies, however, have demonstrated that gene polymorphisms in DC-SIGNR and DC-SIGN affect viral transmission and load in vivo (Liu et al., 2004, 2006; Martin et al., 2004). Homozygosity for L-SIGN-7 was associated with increased risk of HIV-1 infection, while heterozygosity for L-SIGN-7 and -5 conferred protection against infection (Liu et al., 2006). A rare six-repeat form of DC-SIGN (DC-SIGN-6) was shown to confer protection against mucosal infection by HIV-1 (Liu et al., 2004). In another study, a promoter-region polymorphism (336C) in DC-SIGN was associated with an increased risk of parenteral but not mucosal infection by HIV-1 (Martin et al., 2004). The DC-SIGN 336G allele was recently shown to modulate the severity of disease mediated by dengue virus infection (Sakuntabhai et al., 2005). Finally, Nattermann et al. (2006) recently reported that HCV-infected patients carrying L-SIGN alleles 5, 6 and 7 had higher viral loads compared with carriers of alleles 4 and 9. This finding is generally consistent with the pattern of trans-infection that we observed, but for allele 9, which behaves similarly to allele 7. The reasons for this discrepancy could be molecular or immunological and remain to be determined. Overall, the cited reports are consistent with the model whereby capture of pathogens by C-type lectins can assist their dissemination to and infection of target cells (Geijtenbeek et al., 2000b). Our findings support a molecular mechanism whereby genetic polymorphisms could impact diseases caused by HCV and other pathogens recognized by L-SIGN and DC-SIGN.
References
Baribaud, F., Pöhlmann, S., Sparwasser, T. & 13 other authors (2001). Functional and antigenic characterization of human, rhesus macaque, pigtailed macaque, and murine DC-SIGN. J Virol 75, 1028110289.
Bartosch, B., Vitelli, A., Granier, C. & 7 other authors (2003). Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J Biol Chem 278, 4162441630.
Bashirova, A. A., Geijtenbeek, T. B. H., van Duijnhoven, G. C. F. & 10 other authors (2001). A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J Exp Med 193, 671678.
Bergman, M. P., Engering, A., Smits, H. H. & 7 other authors (2004). Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J Exp Med 200, 979990.
Bernhard, O. K., Lai, J., Wilkinson, J., Sheil, M. M. & Cunningham, A. L. (2004). Proteomic analysis of DC-SIGN on dendritic cells detects tetramers required for ligand binding but no association with CD4. J Biol Chem 279, 5182851835.
Boisvert, J., He, X.-S., Cheung, R., Keeffe, E. B., Wright, T. & Greenberg, H. B. (2001). Quantitative analysis of hepatitis C virus in peripheral blood and liver: replication detected only in liver. J Infect Dis 184, 827835.[CrossRef][Medline]
Cambi, A., Gijzen, K., de Vries, I. J. M. & 7 other authors (2003). The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur J Immunol 33, 532538.[CrossRef][Medline]
Colmenares, M., Puig-Kröger, A., Muñiz, P. O., Corbí, A. L. & Rivas, L. (2002). Dendritic-cell (DC)-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN, CD209), a C-type surface lectin in human dendritic cells, is a receptor for Leishmania amastigotes. J Biol Chem 277, 3676636769.
Cooper, S., Erickson, A. L., Adams, E. J., Kansopon, J., Weiner, A. J., Chien, D. Y., Houghton, M., Parham, P. & Walker, C. M. (1999). Analysis of a successful immune response against hepatitis C virus. Immunity 10, 439449.[CrossRef][Medline]
Cormier, E. G., Durso, R. J., Tsamis, F., Boussemart, L., Manix, C., Olson, W. C., Gardner, J. P. & Dragic, T. (2004a). L-SIGN (CD209L) and DC-SIGN (CD209) mediate transinfection of liver cells by hepatitis C virus. Proc Natl Acad Sci U S A 101, 1406714072.
Cormier, E. G., Tsamis, F., Kajumo, F., Durso, R. J., Gardner, J. P. & Dragic, T. (2004b). CD81 is an entry coreceptor for hepatitis C virus. Proc Natl Acad Sci U S A 101, 72707274.
Feinberg, H., Guo, Y., Mitchell, D. A., Drickamer, K. & Weis, W. I. (2005). Extended neck regions stabilize tetramers of the receptors DC-SIGN and DC-SIGNR. J Biol Chem 280, 13271335.
Fournier, C., Sureau, C., Coste, J., Ducos, J., Pageaux, G., Larrey, D., Domergue, J. & Maurel, P. (1998). In vitro infection of adult normal human hepatocytes in primary culture by hepatitis C virus. J Gen Virol 79, 23672374.[Abstract]
Fry, D. E. & Flint, L. M., Jr (1997). Hepatitis: an overview of important issues. Bull Am Coll Surg 82, 813.[Medline]
Gardner, J. P., Durso, R. J., Arrigale, R. R., Donovan, G. P., Maddon, P. J., Dragic, T. & Olson, W. C. (2003). L-SIGN (CD209L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci U S A 100, 44984503.
Garry, R. F. & Dash, S. (2003). Proteomics computational analyses suggest that hepatitis C virus E1 and pestivirus E2 envelope glycoproteins are truncated class II fusion proteins. Virology 307, 255265.[CrossRef][Medline]
Geijtenbeek, T. B., Torensma, R., van Vliet, S. J., van Duijnhoven, G. C., Adema, G. J., van Kooyk, Y. & Figdor, C. G. (2000a). Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100, 575585.[CrossRef][Medline]
Geijtenbeek, T. B. H., Kwon, D. S., Torensma, R. & 9 other authors (2000b). DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100, 587597.[CrossRef][Medline]
Geijtenbeek, T. B. H., van Vliet, S. J., Koppel, E. A., Sanchez-Hernandez, M., Vandenbroucke-Grauls, C. M. J. E., Appelmelk, B. & van Kooyk, Y. (2003). Mycobacteria target DC-SIGN to suppress dendritic cell function. J Exp Med 197, 717.
Gramberg, T., Zhu, T., Chaipan, C., Marzi, A., Liu, H., Wegele, A., Andrus, T., Hofmann, H. & Pöhlmann, S. (2006). Impact of polymorphisms in the DC-SIGNR neck domain on the interaction with pathogens. Virology 347, 354363.[CrossRef][Medline]
Guo, Y., Atkinson, C. E., Taylor, M. E. & Drickamer, K. (2006). All but the shortest polymorphic forms of the viral receptor DC-SIGNR assemble into stable homo- and heterotetramers. J Biol Chem 281, 1679416798.
Halary, F., Amara, A., Lortat-Jacob, H. & 7 other authors (2002). Human cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell trans-infection. Immunity 17, 653664.[CrossRef][Medline]
Ikeda, M., Sugiyama, K., Mizutani, T., Tanaka, T., Tanaka, K., Sekihara, H., Shimotohno, K. & Kato, N. (1998). Human hepatocyte clonal cell lines that support persistent replication of hepatitis C virus. Virus Res 56, 157167.[CrossRef][Medline]
Klimstra, W. B., Nangle, E. M., Smith, M. S., Yurochko, A. D. & Ryman, K. D. (2003). DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses. J Virol 77, 1202212032.
Knolle, P. A. & Gerken, G. (2000). Local control of the immune response in the liver. Immunol Rev 174, 2134.[CrossRef][Medline]
Lavillette, D., Tarr, A. W., Voisset, C. & 7 other authors (2005). Characterization of host-range and cell entry properties of the major genotypes and subtypes of hepatitis C virus. Hepatology 41, 265274.[CrossRef][Medline]
Lechner, F., Wong, D. K. H., Dunbar, P. R. & 7 other authors (2000). Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 191, 14991512.
Lee, B., Leslie, G., Soilleux, E. & 8 other authors (2001). cis Expression of DC-SIGN allows for more efficient entry of human and simian immunodeficiency viruses via CD4 and a coreceptor. J Virol 75, 1202812038.
Liu, H. & Zhu, T. (2005). Determination of DC-SIGN and DC-SIGNR repeat region variations. Methods Mol Biol 304, 471481.[Medline]
Liu, H., Hwangbo, Y., Holte, S. & 8 other authors (2004). Analysis of genetic polymorphisms in CCR5, CCR2, stromal cell-derived factor-1, RANTES, and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin in seronegative individuals repeatedly exposed to HIV-1. J Infect Dis 190, 10551058.[CrossRef][Medline]
Liu, H., Carrington, M., Wang, C. & 13 other authors (2006). Repeat-region polymorphisms in the gene for the dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related molecule: effects on HIV-1 susceptibility. J Infect Dis 193, 698702.[CrossRef][Medline]
Lozach, P.-Y., Lortat-Jacob, H., de Lacroix de Lavalette, A. & 9 other authors (2003). DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J Biol Chem 278, 2035820366.
Lozach, P.-Y., Amara, A., Bartosch, B., Virelizier, J.-L., Arenzana-Seisdedos, F., Cosset, F.-L. & Altmeyer, R. (2004). C-type lectins L-SIGN and DC-SIGN capture and transmit infectious hepatitis C virus pseudotype particles. J Biol Chem 279, 3203532045.
Martin, M. P., Lederman, M. M., Hutcheson, H. B. & 9 other authors (2004). Association of DC-SIGN promoter polymorphism with increased risk for parenteral, but not mucosal, acquisition of human immunodeficiency virus type 1 infection. J Virol 78, 1405314056.
Marzi, A., Gramberg, T., Simmons, G. & 12 other authors (2004). DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus. J Virol 78, 1209012095.
McKeating, J. A., Zhang, L. Q., Logvinoff, C. & 8 other authors (2004). Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner. J Virol 78, 84968505.
Mitchell, D. A., Fadden, A. J. & Drickamer, K. (2001). A novel mechanism of carbohydrate recognition by the C-type lectins DC-SIGN and DC-SIGNR. Subunit organization and binding to multivalent ligands. J Biol Chem 276, 2893928945.
Mummidi, S., Catano, G., Lam, L., Hoefle, A., Telles, V., Begum, K., Jimenez, F., Ahuja, S. S. & Ahuja, S. K. (2001). Extensive repertoire of membrane-bound and soluble dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN1) and DC-SIGN2 isoforms. Inter-individual variation in expression of DC-SIGN transcripts. J Biol Chem 276, 3319633212.
Nattermann, J., Ahlenstiel, G., Berg, T. & 7 other authors (2006). The tandem-repeat polymorphism of the DC-SIGNR gene in HCV infection. J Viral Hepat 13, 4246.[CrossRef][Medline]
Pileri, P., Uematsu, Y., Campagnoli, S. & 8 other authors (1998). Binding of hepatitis C virus to CD81. Science 282, 938941.
Pohlmann, S., Baribaud, F., Lee, B., Leslie, G. J., Sanchez, M. D., Hiebenthal-Millow, K., Münch, J., Kirchhoff, F. & Doms, R. W. (2001a). DC-SIGN interactions with human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus. J Virol 75, 46644672.
Pöhlmann, S., Soilleux, E. J., Baribaud, F., Leslie, G. J., Morris, L. S., Trowsdale, J., Lee, B., Coleman, N. & Doms, R. W. (2001b). 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 U S A 98, 26702675.
Pöhlmann, S., Zhang, J., Baribaud, F. & 7 other authors (2003). Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J Virol 77, 40704080.
Sakuntabhai, A., Turbpaiboon, C., Casademont, I. & 19 other authors (2005). A variant in the CD209 promoter is associated with severity of dengue disease. Nat Genet 37, 507513.[CrossRef][Medline]
Scarselli, E., Ansuini, H., Cerino, R. & 7 other authors (2002). The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 21, 50175025.[CrossRef][Medline]
Serrano-Gómez, D., Domínguez-Soto, A., Ancochea, J., Jimenez-Heffernan, J. A., Leal, J. A. & Corbi, A. L. (2004). Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin mediates binding and internalization of Aspergillus fumigatus conidia by dendritic cells and macrophages. J Immunol 173, 56355643.
Snyder, G. A., Ford, J., Torabi-Parizi, P., Arthos, J. A., Schuck, P., Colonna, M. & Sun, P. D. (2005). Characterization of DC-SIGN/R interaction with human immunodeficiency virus type 1 gp120 and ICAM molecules favors the receptor's role as an antigen-capturing rather than an adhesion receptor. J Virol 79, 45894598.
Soilleux, E. J., Barten, R. & Trowsdale, J. (2000). DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13. J Immunol 165, 29372942.
Tassaneetrithep, B., Burgess, T. H., Granelli-Piperno, A. & 10 other authors (2003). DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J Exp Med 197, 823829.
Yang, Z.-Y., Huang, Y., Ganesh, L., Leung, K., Kong, W.-P., Schwartz, O., Subbarao, K. & Nabel, G. J. (2004). pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN. J Virol 78, 56425650.
Received 15 March 2006; accepted 5 May 2006.