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.

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.