• Viral membrane fusion is the process by which enveloped viruses enter host cells.
• Fusion is the process of bringing two separate membrane bilayers (virus membrane and host cell membrane) into intimate contact and then merging them into one
• Viral proteins promote the fusion of the virion with the plasma membrane, which then forms a pore, and the virion becomes uncoated to release its genomic cargo into the cytoplasm.
• Specialized viral proteins (fusion-active domain) so-called fusogens, which promote virus-cell membrane fusion can be divided into three classes: (i) class I fusogens, which are dominated by α-helical coils; (ii) class II fusogens, which consist predominantly of β-sheets; and (iii) class III fusogens, which feature both secondary structure types.
• The viral fusogens experience drastic structural rearrangements during fusion, liberating the energy required to overcome the repulsive forces that prevent spontaneous fusion of the two membranes.
• Whether fusion occurs by a low-pH-dependent or a pH-independent process, it usually requires a conformational change of the viral fusion protein just prior to the fusion reaction.

Types of fusion

1. Fusion from without: Virus fusion at the cellular external plasma membrane using a ‘fusion protein’, which mediates fusion. Used by paramyxoviruses (measles and mumps viruses), and also HIV
2. Fusion from within: Some enveloped viruses, such as influenza, achieve release from the internal endosomal vacuole by internal fusion (‘fusion from within’) mediated by the viral fusion protein
3. Cell to cell fusion: Some viruses such as vaccinia virus (VV) and herpes simplex virus (HSV) induce the expression of proteins on the surfaces of infected cells that attract uninfected cells and cause them to fuse with the infected cell at low pH values to form a multinuclear cell known as a syncytium. Syncytium formation represents a very efficient way for a virus to spread within a host: it circumvents the immune response and creates a good site of replication for a nuclear-replicating virus. It should be noted that syncytium formation is not always regarded as an entry mechanism per se.

Steps of the membrane fusion process. (a) Diagram of the fusion steps between two protein-free lipid bilayers. From top to bottom: the lipids (represented by heads and tails) of the two bilayers are initially curved into nipple-like structures that approach the two membranes. This is followed by the formation of the stalk in which the two proximal leaflets are fused. This stalk is then expanded forming a hemifusion diaphragm in which lipids of the distal leaflets of the bilayers are now in direct contact. Finally, rupture of the hemifusion diaphragm leads to the formation of the fusion pore. (b) Diagram of the virus-cell fusion process: As an example, fusion mediated by the influenza HA is illustrated. Left panels: HA is a homotrimer that initially binds to the cell surface (not shown) by interactions of each subunit head with sialic acid. Then, the virus is internalized by endocytosis. For simplicity, only 1 HA trimer in the pre-fusion conformation is shown, anchored into the viral membrane. After endosome acidification, the HA globular head falls apart, allowing refolding of the molecule to produce three long α-helices. The fusion peptides, placed at the N-terminal end of each α-helix, insert into the target membrane. This intermediate, dubbed pre-hairpin, refolds to bring the two membranes into proximity leading to the formation of the lipid stalk followed by the formation of the hemifusion diaphragm (not shown). Finally, the fusion pore is formed by the concerted action of several HA molecules that adopt a very stable post-fusion conformation. Right panels: The upper panel shows a mixture of an influenza virus particle (strain X31, H3N2, white arrow) and liposomes (some of them indicated by white arrowheads) made with lipids commonly found in cell membranes, incubated at neutral pH. Note the glycoprotein spikes (mostly haemagglutinin, HA) sticking out of the viral membrane in contrast with the smooth surface of liposomes. The middle panel shows the same virus/liposome mixture after incubation for 5–10 s at pH 5.0 followed by neutralization. Note binding of liposomes to the virus surface and initiation of virus-liposome fusion. The lower panel shows the virus/liposome mixture after incubation for 5 min at pH 5.0 followed by neutralization. Note that the virus has fused with several liposomes, yielding a large vesicle with viral glycoproteins dispersed throughout the surface and with a small liposome still in the process of fusion. The HA spikes also have changed morphology after exposure to low pH and fusion. (Courtesy of L.J. Calder and S.A. Wharton, Division of Virology, MRC National Institute for Medical Research, London, UK). (c) Diagram of vesicle fusion at the synaptic junction: Initially one of the SNARE proteins (synaptobrevin, blue) is inserted into the vesicle membrane, while three other SNAREs (two SNAP 25, green, and one syntaxin, red) are inserted in the plasma membrane. After an initial interaction, refolding of the SNAREs leads to the formation of a bundle of four parallel α-helices that drives approximation of the two membranes and formation of the stalk and hemifusion intermediates (not shown). Completion of the SNARE complex results in the formation of the fusion pore. In the two lower panels of parts (b) and (c), two HAs and two SNARE complexes are shown surrounding the fusion pore, although the actual number of molecules involved in fusion pore formation is likely to be higher. See this image and copyright information in PMC.