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Virus entry: molecular mechanisms and biomedical applications

Nature Reviews Microbiology volume 2, pages 109–122 (2004)Cite this article

Key Points

  • Virus entry into animal cells is initiated by attachment to receptors and is followed by important conformational changes of viral proteins, penetration through (non-enveloped viruses) or fusion with (enveloped viruses) cellular membranes. The process ends with transfer of viral genomes inside host cells.

  • Viral proteins mediating entry are very diverse, but many share common three-dimensional structural motifs.

  • Conformational changes in the viral proteins that drive entry are typically initiated by high-affinity interactions with receptors, or changes in pH after receptor binding and internalization. They include formation of coiled-coils in class I fusion proteins, dimer to trimer transitions in class II fusion proteins, movement of capsid proteins in non-enveloped viruses and exposure of membrane destabilizing sequences.

  • Fusion with, or penetration through, cell membranes might involve multimolecular protein complexes and requires structural rearrangements of membrane lipids.

  • Inhibitors of virus entry can prevent virus attachment, or bind to entry intermediates; small organic molecules, peptides, soluble receptors and antibodies are in clinical trials. Six virus-specific polyclonal human immunoglobulins, one monoclonal antibody and one peptide have been approved by the US Food and Drug Administration for clinical use.

  • Viral proteins involved in entry can induce immune responses and be used as vaccine immunogens.

  • Viral entry machineries could be beneficial for human physiology and retargeted for the treatment of cancer and other diseases.

Abstract

Viruses have evolved to enter cells from all three domains of life — Bacteria, Archaea and Eukaryotes. Of more than 3,600 known viruses, hundreds can infect human cells and most of those are associated with disease. To gain access to the cell interior, animal viruses attach to host-cell receptors. Advances in our understanding of how viral entry proteins interact with their host-cell receptors and undergo conformational changes that lead to entry offer unprecedented opportunities for the development of novel therapeutics and vaccines.

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Figure 1: Two main virus entry pathways.
Figure 2: Structure of virus surfaces.
Figure 3: Structures of soluble fragments from virus entry proteins.
Figure 4: Receptor recognition.
Figure 5: Conformational changes of viral fusion proteins leading to membrane fusion.

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Acknowledgements

I thank R. Blumenthal, C. Broder, P. Kwong and the three reviewers for helpful comments, and members of my group, X. Xiao, M. Zhang, I. Sidorov and P. Prabakaran, for exciting discussions and help. I apologise to those colleagues whose research has not been highlighted owing to length constraints. The selected examples reflect my personal interests.

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  1. Human Immunovirology and Computational Biology Group, Laboratory of Experimental and Computational Biology, Centre for Cancer Research, Building 469, Room 246, Miller Drive, National Cancer Institute at Frederick, Frederick, 21702-1201, Maryland, USA

    Dimiter S. Dimitrov

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DATABASES

LocusLink

CCR5

CD4

CXCR4

Protein Data Bank

gp120

influenza haemagglutinin

FURTHER INFORMATION

Dimiter S. Dimitrov's laboratory

HIV fusion and cell entry

Picornavirus infection and translation

The Big Picture Book of Viruses

Glossary

ENTRY PROTEINS

Proteins that mediate entry into cells. Entry proteins is a general term used here to denote attachment proteins and other proteins that are required for entry of non-enveloped and enveloped viruses into cells.

LIPID RAFT

Areas of the plasma membrane that are rich in cholesterol, glycosphingolipids and glycosylphosphatidylinositol-anchored proteins. Also known as glycolipid-enriched microdomains (GEMs) and detergent-insoluble glycolipid-enriched membranes (DIGs).

LIPOSOME

A lipid vesicle that is artificially formed by sonicating lipids in an aqueous solution.

METASTABLE STATE

An energy state that is separated from one of lower energy by an energy barrier. Metastable states can exist for a long time if the height of the barrier is high and be undistinguishable from a truly stable state. The trigger leads to a decrease in the energy barrier and a transition to a more stable state of lower energy. The rate of transition is determined by the difference in the energies of the initial and final states, temperature and various parameters including molecular conformations and viscosity.

ATTACHMENT PROTEINS

Proteins that mediate specific binding of viruses to their receptors. Attachment proteins are typically single proteins but in the case of many non-enveloped viruses, complexes of several proteins from the capsid bind receptor molecules and function as attachment proteins.

CAPSID

Proteins that encapsulate viral genomes. Capsid shells of many non-enveloped viruses proteins bind receptor molecules and serve as attachment proteins. Capsid proteins also typically mediate membrane penetration by non-enveloped viruses.

ENVELOPE GLYCOPROTEINS

(Envs). Viral proteins that are embedded in the envelope membranes of enveloped viruses. Many viruses, for example, rabies virus and HIV, have only one viral protein in their membranes that mediates viral entry into cells; others, for example, influenza have two or more, but some of the proteins might not be involved in the entry process. In this article, Envs is used to describe those entry proteins that mediate attachment and fusion of enveloped viruses.

FUSION PROTEINS

Proteins that mediate the fusion of enveloped viruses. This term is frequently used to denote entry proteins that mediate the membrane fusion of enveloped viruses, for example, class I and class II fusion proteins. Typically, such proteins consist of an attachment protein (subunit or domain), sometimes denoted as surface protein, and a subunit mediating the actual membrane fusion event, sometimes denoted as transmembrane protein because it spans the viral membrane.

VIRUS RECEPTORS

Host-cell molecules (usually membrane-associated) that bind virus-attachment proteins and are required for entry.

AVIDITY

Effective affinity for multivalent interactions. Avidity is a complex function of the affinity for a monovalent interaction and the number of interactions, and can be many orders of magnitude higher than affinity.

CO-RECEPTORS

Cell membrane-associated molecules that bind specifically to virus proteins and are required for entry (in addition to the primary receptor) typically to ensure continuation of the entry process after binding. By definition the term co-receptor implies a physical association with viral entry proteins after their binding to the primary receptor to distinguish them from molecules that are required for entry at later stages — for example, uncoating — or at unknown stages, and are denoted as entry cofactors.

ALTERNATIVE VIRUS RECEPTORS

Receptors that viruses can use in the absence of the primary receptor, typically with a much lower efficiency for entry.

CYTOPATHIC EFFECTS

(CPE). Effects caused by any agent, including viruses, that lead to deterioration of cellular functions and ultimately cell death.

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Dimitrov, D. Virus entry: molecular mechanisms and biomedical applications. Nat Rev Microbiol 2, 109–122 (2004). https://doi.org/10.1038/nrmicro817

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