Neutralization of Virus Infectivity by Antibodies: Old Problems in New Perspectives

Figure 1

The mechanism of neutralization. Neutralization of enveloped viruses blocks viral attachment and entry. No other mechanisms are yet known; but entry can be blocked at different stages. The three blue virions to the right represent enveloped virus particles. The first has an IgG bound to its receptor-binding protein (green, for simplicity shown as a single copy). The bound NAb blocks the docking onto the receptor (grey) on the cell surface. The second virion has already established contact between its receptor-binding protein and the cell-surface receptor. The NAb binds to an epitope on the envelope glycoprotein (viral proteins with this function and topology are usually glycosylated) that may have become exposed after the receptor binding and blocks subsequent steps; these could be interactions with a second receptor or the fusogenic refolding of the envelope glycoprotein. The third blue virion is about to fuse with the cell membrane, but NAbs bound to membrane proximal epitopes on fusogenic proteins (not shown) prevent the completion of this process. The latter two interferences with entry could also occur in endosomes, but hardly the first, unless there are alternative attachment proteins the virus can bind to and thereby get internalized. The purple virion in the endosome is prevented by NAbs from fusing its envelope with the vesicular membrane. Alternatively, this purple virion could represent a naked virus particle, the penetration of which is prevented by the NAbs. The block of infection in the endosome could properly be called a postinternalization block of entry; for clarity, entry should refer to transfer of the viral core or capsid, or possibly only genome, into the cytoplasm. The red virion on the cell surface depicts a naked virion that binds to a cell surface receptor and injects the genome into the cytoplasm. This process may occur in vesicles or semisealed invaginations of the cell surface. If the NAbs have not prevented receptor interactions, they may interfere with the extrusion of the genome. The red virion in the cytoplasm has penetrated an endosomal membrane in complex with the NAb, allowing binding to TRIM21 (yellow box with arrow), which mediates the ubiquitination of the complex, targeting it for proteasomal degradation. This fairly recently discovered effect constitutes the clearest example so far of a postentry mechanism of neutralization.