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

Key Points

  • 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.

Abstract

Herpesviruses are double-stranded DNA, enveloped viruses that infect host cells through fusion with either the host cell plasma membrane or endocytic vesicle membranes. Efficient infection of host cells by herpesviruses is remarkably more complex than infection by other viruses, as it requires the concerted effort of multiple glycoproteins and involves multiple host receptors. The structures of the major viral glycoproteins and a number of host receptors involved in the entry of the prototypical herpesviruses, the herpes simplex viruses (HSVs) and Epstein–Barr virus (EBV), are now known. These structural studies have accelerated our understanding of HSV and EBV binding and fusion by revealing the conformational changes that occur on virus–receptor binding, depicting potential sites of functional protein and lipid interactions, and identifying the probable viral fusogen.

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Figure 1: Herpesvirus entry.
Figure 2: Receptor-binding proteins of Epstein–Barr virus and herpes simpex viruses, in bound and unbound states.
Figure 3: Conserved entry complex glycoprotein H (gH)–gL.
Figure 4: Conserved fusion protein glycoprotein B.
Figure 5: Models of herpes simplex virus and Epstein–Barr virus fusion.

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Acknowledgements

Research in the Jardetzky and Longnecker laboratories was supported by US Public Health Service grants (AI076183 and CA117794 to T.S.J., and AI076183, CA117794 and AI067048 to R.L.). The authors thank current and former members of their laboratories for their contributions to the work described, as well as their many colleagues throughout the world who have contributed to understanding the entry of EBV, HSV and other herpesviruses.

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Glossary

Enveloped viruses

Viruses that contain a phospholipid membrane surrounding the viral protein coat when they are outside of the host cell.

Latent infections

Persistent viral infections that can occur in some cell types; during these infections, the virus ceases to replicate but limited expression of some viral genes (a 'latent-phase transcriptional programme') still occurs.

Endocytic vesicle

A membrane-bound vesicle that participates in the endocytic membrane transport pathway from the plasma membrane (the outer membrane of a cell) to the lysosome (a membrane-bound organelle containing digestive enzymes that can, among other things, degrade invading bacteria and viruses).

Cell tropism

The preferential targeting of specific cell types within a host by a pathogen.

Heterodimer

A compound consisting of two non-identical subunits (in this case, a dimer composed of one gH molecule and one gL molecule).

Proteoglycans

Proteins that contain an abundance of sugars, including one or more glycosaminoglycan chains, on their surface.

C-type lectin superfamily

A large family of functionally diverse proteins containing conserved structures of double loops that are stabilized by disulphide bridges; these structures are termed C-type lectin-like domains.

Hydrophobic pocket

A groove or pocket in a protein that typically serves as a binding site and is composed of mostly hydrophobic amino acid residues.

Heptad repeats

Structural motifs in the amino acid sequence of proteins, typically signalling the formation of a coiled coil, a structure that is common to viral fusion proteins.

Fusion peptides

Sequences of hydrophobic residues within a fusion protein; these sequences insert into a target cell membrane during the fusion event.

Epitope

The portion of an antigen (a protein that is capable of eliciting an immune response) which is recognized by a specific antibody directed against that antigen.

Fusion loops

Loops composed of hydrophobic residues that are present in class II and class III fusogens and perform the same function as the fusion peptides present in class I fusogens.

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Connolly, S., Jackson, J., Jardetzky, T. et al. Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol 9, 369–381 (2011). https://doi.org/10.1038/nrmicro2548

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