The cell biology of receptor-mediated virus entry

Grove, Joe; Marsh, Mark

ltivesicular body. Krummenacher, 2008; Burckhardt et al., 2011) . Simply, the use of multiple receptors will increase binding avidity, but, of more consequence, the sequential engagement of distinct receptor moieties allows the timing of key events in virus fusion/penetration to be tightly coordinated (López and Arias, 2004; Burckhardt et al., 2011) . Although viruses have the potential to cluster homogenous or heterogenous receptors, we know relatively little of the stoichiometry of receptor engagement. How viruses assemble multimeric receptor complexes on the surfaces of cells and the impacts that variations in this process have on fusion/ penetration dynamics, sites of entry, and subsequent uncoating remain poorly understood. Lateral motion on the cell surface or along filopodia has been observed for several viruses and may help viruses encounter necessary coreceptors in numbers sufficient to generate productive entry events (Lehmann et al., 2005; Burckhardt and Greber, 2009 ). Alternatively, it may bring viruses to positions of endocytosis or where fusion/penetration is more likely to lead to productive infection. High-resolution mapping of most cell surface receptors by EM, super-resolution light nanoscopy, and live-cell single-molecule tracking remains to be performed. In the case of virus receptors, mapping the infection (Harris et al., 2008 . HCV requires clathrinmediated endocytosis and low endosomal pH for productive infection (Blanchard et al., 2006; Meertens et al., 2006; Tscherne et al., 2006) . That HCV uses such a complex array of cell surface components to achieve this goal suggests that receptor engagement plays a more substantial role in virus entry than just guiding virions into clathrin-coated vesicles. Hints that this may be the case include the observation that HCV particles associate with host lipoproteins that bind both SR-B1 and/or the LDLR and that SR-B1 can facilitate the bidirectional transport of cholesterol from lipoproteins, raising the possibility that virion-associated lipoproteins can locally modify the lipid environment of a host cell membrane (Scarselli et al., 2002; Shimizu et al., 2011) . In addition, HCV entry can be modulated by receptor tyrosine kinases (EGF receptor [EGFR] and EphA2), possibly through mechanisms that influence CD81 interaction with claudin-1 (Lupberger et al., 2011) .