Tetraspanins: CD81 and claudin-1

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Tetraspanins are widely expressed proteins that regulate cell morphology, motility, invasion, fusion and signalling (46). These proteins contain four transmembrane domains, short intracellular domains and two extracellular loops, namely the small extracellular loop and the large extracelullar loop (LEL). CD81 has been identified as an HCV E2 binding molecule by expression cloning (13) using a cDNA library derived from a subclone of the human T cell lymphoma cell line Molt-4, which exhibits a high E2-binding capacity (25). Anti-CD81 antibodies as well as a soluble form of CD81 LEL have been shown to inhibit HCVpp and HCVcc entry into Huh-7 hepatoma cells and human heptocytes (9, 17-20, 45, 47, 48). Furthermore, silencing of CD81 expression in hepatoma cells by small interfering RNAs inhibited HCVpp entry as well as HCVcc infectivity and expression of CD81 in hepatoma cell lines that are resistant to HCVpp and HCVcc infection conferred susceptibility to HCV infection (22, 45, 47, 49). In addition, it has been demonstrated that CD81 expression levels on hepatoma cells correlate with HCV infectivity (49, 50). These results suggest that susceptibility to HCV infection may be linked to CD81 density on the cell surface and thus provide an explanation for HCV tissue tropism in vivo. Interestingly, CD81 from HCV refractory species are able to bind HCV E2 (51) and CD81 of various species may confer susceptibility to HCV infection (52) suggesting that CD81 is not the determinant for the species specificity of HCV. Recent studies using the HCVpp and HCVcc model system demonstrated the ability of anti-CD81 antibodies to inhibit HCV entry at a step post binding (35, 53) suggesting that CD81 functions as an HCV entry co-receptor after docking of the virus to attachment molecules. Most recently, another member of the tetraspanin family claudin-1 (CLDN1), has been identified as an HCV co- entry factor by expression cloning (39). CLDN1 is highly expressed in the liver but also in other tissues (54). However, CLDN1 expression correlates with HCV permissiveness and expression of CLDN1 in non-hepatic 293T cells renders them susceptible to HCVpp entry (39). In addition, overexpression of this molecule in CD81-deficient HepG2 hepatoma cells did increase their HCV permissivity, suggesting that CLDN1 is not an alternative entry pathway to CD81 (39). In addition, kinetic studies showed that CLDN1 acts at a post binding step after HCV interaction with CD81 (39). As tetraspanins are able to form associations with a wide variety of proteins as well as cholesterol and gangliosides (46), this suggests that several HCV co-receptors may be recruited to discrete membrane domains allowing the formation of an HCV entry receptor complex. Interestingly, murine CLDN1 also supports HCVpp entry, demonstrating that CLDN1, as CD81, is not a determinant for species host range (39).