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The structural basis of herpesvirus entry

Nature Reviews Microbiology volume 19, pages 110–121 (2021)Cite this article

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Abstract

Herpesviruses are ubiquitous, double-stranded DNA, enveloped viruses that establish lifelong infections and cause a range of diseases. Entry into host cells requires binding of the virus to specific receptors, followed by the coordinated action of multiple viral entry glycoproteins to trigger membrane fusion. Although the core fusion machinery is conserved for all herpesviruses, each species uses distinct receptors and receptor-binding glycoproteins. Structural studies of the prototypical herpesviruses herpes simplex virus 1 (HSV-1), HSV-2, human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) entry glycoproteins have defined the interaction sites for glycoprotein complexes and receptors, and have revealed conformational changes that occur on receptor binding. Recent crystallography and electron microscopy studies have refined our model of herpesvirus entry into cells, clarifying both the conserved features and the unique features. In this Review, we discuss recent insights into herpesvirus entry by analysing the structures of entry glycoproteins, including the diverse receptor-binding glycoproteins (HSV-1 glycoprotein D (gD), EBV glycoprotein 42 (gp42) and HCMV gH–gL–gO trimer and gH–gL–UL128–UL130–UL131A pentamer), as well gH–gL and the fusion protein gB, which are conserved in all herpesviruses.

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Fig. 1: Model of the herpesvirus entry mechanism.
Fig. 2: Herpes simplex virus 1 glycoprotein D crystal structures.
Fig. 3: Epstein–Barr virus glycoprotein 42 structures.
Fig. 4: Structures of human cytomegalovirus glycoprotein H–glycoprotein L complexes.
Fig. 5: Crystal structures of the glycoprotein H–glycoprotein L complex.
Fig. 6: Glycoprotein B structures.

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Acknowledgements

This work was supported by grants AI-137267 and AI-148478 from the US National Institute of Allergy and Infectious Diseases of the National Institutes of Health. All crystal structures in this Review were rendered with MacPyMOL.

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Authors and Affiliations

  1. Department of Health Sciences, DePaul University, Chicago, IL, USA

    Sarah A. Connolly

  2. Department of Structural Biology, Stanford University School of Medicine, Stanford University, CA, USA

    Theodore S. Jardetzky

  3. Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Richard Longnecker

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  1. Sarah A. Connolly
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  2. Theodore S. Jardetzky
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  3. Richard Longnecker
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The authors contributed equally to all aspects of the article.

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Correspondence to Sarah A. Connolly or Richard Longnecker.

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Nature Reviews Microbiology thanks A. Carfi, K. Grünewald, A. Nicola, L. Perez, B. Vollmer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

EMDataResource: http://www.emdataresource.org/

RCSB Protein Data Bank: https://www.rcsb.org/

Glossary

Enveloped viruses

Viruses with an outer layer consisting of a lipid bilayer, in which the viral glycoproteins responsible for mediating virus entry into cells are embedded.

Conformational changes

Changes in protein structure made possible by the intrinsic flexibility of the protein that can be triggered by environmental factors, such as binding to a receptor or another glycoprotein.

Entry receptors

Molecules present in host cells that bind directly to viruses and mediate virus entry into the cell.

Cell tropism

The specific cell types that support the replication of different viruses.

Crystal structures

Structural models based on X-ray diffraction of a crystal that often permit atomic resolution for protein structures.

Neutralizing monoclonal antibodies

(nAbs). Antibodies that bind to a virus particle and prevent infection, typically by preventing virus entry into the cell.

Fusion loops

Short stretches of hydrophobic residues within a fusion protein that insert themselves into the host cell membrane during the fusion event.

Cryo-electron tomography

(cryo-ET). Method to produce high-resolution 3D models of molecules held at cryogenic temperature by reconstructing a series of 2D electron microscopy images taken from multiple angles.

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Connolly, S.A., Jardetzky, T.S. & Longnecker, R. The structural basis of herpesvirus entry. Nat Rev Microbiol 19, 110–121 (2021). https://doi.org/10.1038/s41579-020-00448-w

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