Dynamics of virus-receptor interactions in virus binding, signaling, and endocytosis

Abstract

During viral infection the first challenge that viruses have to overcome is gaining access to the intracellular compartment. The infection process starts when the virus contacts the surface of the host cell. A complex series of events ensues, including diffusion at the host cell membrane surface, binding to receptors, signaling, internalization, and delivery of the genetic information. The focus of this review is on the very initial steps of virus entry, from receptor binding to particle uptake into the host cell. We will discuss how viruses find their receptor, move to sub-membranous regions permissive for entry, and how they hijack the receptor-mediated signaling pathway to promote their internalization.

Keywords: binding; endocytosis; signalization; single particle tracking; uptake; virus receptor.

Figure 1

Strategies of virus entry. To gain access to the cytoplasm of host cells, viruses can employ two main strategies, i.e., either (A) through endocytosis and escape from endosomal vesicles in a process referred as receptor-mediated endocytosis or (B) by direct penetration from the plasma membrane, referred as endocytosis-independent receptor-mediated entry. Enveloped viruses are shown; however non-enveloped viruses have evolved similar strategies. These are just generalizations and there are exemptions from these rules. Black arrows represent the sequence of events and dashed-red arrows the potential induced signaling.

Figure 2

How viruses find their receptor(s). Viruses have evolved different strategies to interact with their receptor(s) at the surface of host cells. (A) After landing on the cell surface and binding to receptor(s), some viruses remain stick at a confined location from where they will be endocytosed in a passive or signal-induced manner; (B) Others, after binding to their receptor, will diffuse at the cell surface seeking additional receptor molecules. The virus/receptor complex will be then spatially confined in a host plasma membrane microdomain from where it will be endocytosed; (C) Some viruses, following binding to their receptors, diffuse at the surface of the host cell seeking for preformed endocytic structures that they hijack to mediate their internalization; (D) Viruses can land on the surface of the cells and bind to a primary receptor. This initial binding induces signaling that leads to active redistribution of the virus/primary receptor complex seeking for a secondary receptor that mediates virus uptake. Abbreviations: CAR, coxsackievirus and adenovirus receptor; CBV, group B coxsackievirus; CPV, canine parvovirus; DAF, CBV co-receptor; DV, dengue virus; mPy, mouse Polyomavirus; SV40, simian polyomavirus 40; VSV, vesicular stomatitis virus.

Figure 3

Signaling during virus entry. Infections cause profound perturbations of the host cell signaling networks. Signaling likely begins at the plasma membrane, after virus binding to receptors. Here are few examples of signaling during virus entry. (A) Following attachment at the cell surface, influenza A virus (IAV) relies on the activation of epidermal growth factor receptor (EGFR) for the endocytosis of virions. However, no direct interaction has been reported between IAV and EGFR; (B) In the case of vaccinia virus (VV), virions seem to cooperate for entry. In this model, the first incoming virions trigger signaling through binding to primary receptor(s). The signal facilitates the recruitment of other receptors, which all together mediate the attachment and endocytosis of further incoming particles by induction of micropinocytosis; (C) Upon binding of viruses to receptor molecules, receptor-mediated signaling induces the local internalization of the virus/receptor complex. Concrete evidence supporting such receptor-mediated signaling that results in an active internalization is missing. The encircled numbers indicate the sequence of events.

Figure 4

Endocytic signals in virus receptors. Relatively few endocytic signals in receptors have been assessed for their role in virus entry and infection. (A) The LL motif of DC-SIGN is critical for Uukuniemi virus (UUKV) internalization and acts as endocytic motif; (B) The two NPXY motifs in the β1-integrin (β1) seem to act as sorting motifs to direct reovirus into the right endosomal compartment; (C) No function has been attributed to the YNQV motif in CAR regarding infection by adenovirus 5 (Ad5).