The cell biology of receptor-mediated virus entry

Grove, Joe; Marsh, Mark

Many mammalian viruses initially gain access to their hosts by crossing epithelial barriers in the respiratory, digestive, or reproductive tracts, either with or without infection of the epithelial cells themselves. Although these epithelial tissues act as barriers between body cavities and underlying tissues, viruses have become adept at finding ways across. Some viruses exploit cells of the immune system, such as macrophages and dendritic cells, which have innate capacities to cross or extend processes across epithelia, as "Trojan horses" to penetrate the epithelial barrier (Shannon-Lowe et al., 2006; Stamataki et al., 2009; Lemon et al., 2011) . Others have developed remarkable capacities to exploit epithelial cell surface proteins. The entry of coxsackievirus B provides a striking example. This virus infects its human hosts through the epithelial lining of the gut. For infection of polarized epithelial (Caco-2) cells in culture, coxsackievirus B requires the coxsackievirus and adenovirus receptor (CAR), which is located on the basolateral surface and within tight junctions and is inaccessible to apically delivered viruses (Cohen et al., 2001) . The virions initially bind to an apically expressed glycosylphosphatidylinositol-linked protein, CD55/ decay-accelerating factor (DAF), the clustering of which activates Abl kinase and drives Rac-dependent actin reorganization that in turn leads to translocation of virus particles to tight junctions where they engage CAR and undergo endocytosis (Coyne and Bergelson, 2006) . Binding to CD55 also activates the nonreceptor tyrosine kinase Fyn, which phosphorylates caveolin, thus facilitating endocytosis (Coyne and Bergelson, 2006) . As CD55 cannot link directly to the actin cytoskeleton, it is unclear how actin-dependent translocation of virus-receptor complexes occurs, nor is it clear how the virus transits tight junctions and undergoes endocytosis. Nevertheless, this system provides an Figure 2 . Virus receptors. Virus entry is initiated by specific interactions between virus particles and receptors. (A) Human rhinovirus 2 undergoes receptormediated endocytosis after interaction with LDLR. (B) CD4 is the primary receptor for HIVs, but virus penetration requires further interactions with chemokine receptor CCR5 or CXCR4. Initial observations indicated that coreceptor engagement triggered fusion directly at the plasma membrane; however, recent studies suggest that fusion can also occur after endocytosis (Miyauchi et al., 2009) . Although these mechanisms appear mutually exclusive, it is possible that both may operate, and additional studies are required to establish the relevant pathway for key target cells in vivo. (C) HCV entry requires at least four host factors. The virus particle is thought to directly interact with SR-B1 and CD81, whereas the tight junction components claudin-1 and occludin are indirectly involved. Data suggest that CD81/claudin-1 heteromers are necessary for infection. It is currently unknown how HCV is directed to clathrin-coated vesicles. et al., 2003) . Clathrin-mediated endocytosis is also required for DC-SIGN-mediated uptake of phleboviruses, with endocytic sorting signals in the N-terminal cytoplasmic domain of DC-SIGN being essential for endocytosis and infection (Lozach et al., 2011b) .