The cell biology of receptor-mediated virus entry

Grove, Joe; Marsh, Mark

Another intriguing example of a virus requiring multiple cell surface components for entry is hepatitis C virus (HCV). Aside from attachment factors that include heparan sulfate and L-SIGN (Barth et al., 2003; Gardner et al., 2003; Pöhlmann et al., 2003) , the HCV envelope glycoprotein E2 interacts directly with two receptors: the tetraspanin CD81 that is thought to be involved in membrane microdomain architecture (Pileri et al., 1998) and SR-B1 that binds several lipoproteins, including high-density lipoprotein, low-density lipoprotein, and very lowdensity lipoprotein (Scarselli et al., 2002) . In addition to these key components, the minimal HCV entry complex requires the tight junction components claudin-1 and occludin. Thus, coexpression of four proteins-CD81, SR-B1, claudin-1, and occludin-is required to confer permissivity for HCV entry (Fig. 2 C; Evans et al., 2007; Liu et al., 2009; Ploss et al., 2009; Dorner et al., 2011) . There is limited evidence for a direct interaction between the HCV glycoproteins and claudin-1 or occludin (Evans et al., 2007; Krieger et al., 2010) , indicating that these molecules may act by regulating the activities of CD81 and/or SR-B1 rather than binding viruses directly; indeed, heterodimers of claudin-1 and CD81 may be necessary for single molecular species as receptors, for example CD155 for poliovirus (Mendelsohn et al., 1989) , the low-density lipoprotein receptor (LDLR) for human rhinovirus 2 (Fig. 2 A; Hofer et al., 1994) , and dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) for the phleboviruses (a subgroup of bunyaviruses; Lozach et al., 2011b) . Alternatively, some viruses can use more than one molecular species as receptors, each with equivalent roles, for example, angiotensinconverting enzyme (ACE) or liver-SIGN (L-SIGN) for SARS coronavirus (Li et al., 2003; Jeffers et al., 2004) and scavenger receptor-B2 (SR-B2) or P-selectin glycoprotein ligand-1 (PSGL-1) for enterovirus 71 (Table I; Nishimura et al., 2009; Yamayoshi et al., 2009) . However, other viruses exhibit a more complex receptor dependency that involves engagement with at least two distinct plasma membrane components, each of which is essential (Fig. 2) . Human immunodeficiency viruses (HIVs) are the archetype for such a process. After adsorption to cell surface attachment factors, the HIV envelope protein (Env, consisting of trimers of gp120/gp41 heterodimers) binds to the primary receptor CD4 (Dalgleish et al., 1984; Klatzmann et al., 1984) . By relieving constraints that prevent Env from transitioning to thermodynamically more stable conformations, these interactions initiate conformational changes that facilitate strain-specific interactions of gp120 with the coreceptors CCR5 or CXCR4 and allow initial structural changes in gp41, the Env component that promotes Figure 1 . Virus entry strategies. The cell imposes intrinsic barriers to virus entry including the plasma membrane, actin cortex, and limiting intracellular membranes. (A and B) Viruses have evolved various strategies to overcome these barriers, such as receptor-mediated endocytosis followed by pH-dependent/ independent fusion from endocytic compartments (A) or pH-independent fusion at the plasma membrane, coupled with receptor-mediated signaling and coordinated disassembly of the actin cortex (B). Enveloped viruses are shown; nonenveloped viruses use similar strategies, although the mechanisms of action are different. MVB, mu