Fusing structure and function: a structural view of the herpesvirus entry machinery

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Abstract
Herpesviruses are a ubiquitous, large, diverse family of double-stranded DNA, enveloped viruses that are capable of infecting a wide range of hosts and causing a variety of diseases. Prototypical herpesviruses are herpes simplex virus 1 (HSV-1), HSV-2 and Epstein–Barr Virus (EBV), which cause oral herpes, genital herpes and mononucleosis, respectively. Herpesviruses use common mechanisms to bind to and enter target cells through a process of virus-induced membrane fusion. Relative to other enveloped viruses, herpesviruses require a large number of glycoproteins in order to accomplish fusion. The conserved core set of glycoproteins required for entry are glycoprotein B (gB) and a heterodimer composed of gH and gL, referred to as gH–gL. Additional required glycoproteins are the receptor-binding proteins gD from HSVs and glycoprotein 42 (gp42) from EBV. The structures for each glycoprotein required for virus entry, as well as for three of the cellular receptors that bind to the virus and/or trigger fusion, are now known. EBV and HSVs infect multiple cell types through engagement with different receptors. Although the primary receptor-binding proteins of these viruses are different, fusion of HSVs and EBV with most cell types is triggered when their receptor-binding proteins bind a receptor via flexible amino-terminal extensions. A resulting conformational change is thought to trigger the viral glycoproteins that execute fusion. Viral glycoproteins that execute fusion — gB and gH–gL — are conserved within the herpesvirus family. The crystal structure of gB revealed that it is a viral fusion protein that is capable of inserting into target membranes and inducing fusion through conformational changes. The specific role of gH–gL in fusion has eluded researchers for years. Evidence suggested that it was an additional fusion protein, but the recently solved structure of HSV-2 gH–gL revealed, surprisingly, that it does not resemble any known fusion protein. A new model of herpesvirus fusion is emerging in which gH–gL acts as a regulator of gB through (gH–gL)–gB interaction. Herpesvirus fusion is a remarkably complex process. Now that the structures of all the major glycoproteins and receptors involved in herpesvirus fusion are known, they can be used for the rational design of novel attachment and fusion inhibitors against these ubiquitous human pathogens.