Hemagglutinin (influenza) - Neutralizing Antibodies

Neutralizing Antibodies

Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies. Neutralizing antibodies against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin:

1. Inhibition of attachment to target cells
2. Inhibition of membrane fusion (entry)

Most commonly, antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure at right) and physically block the interaction with sialic acid receptors on target cells. In contrast, some antibodies have been found to have no effect on attachment. Instead, this latter group of antibodies acts by preventing membrane fusion. Most of these antibodies, like the human antibodies F10, FI6, CR6261, recognize sites in the stem/stalk region region (orange region in figure at right), far away from the receptor binding site.

The stem (also called HA2), contains most of the membrane fusion machinery of the hemagglutinin protein, and antibodies targeting this region block key structural changes that drive the membrane fusion process. However, at least one fusion-inhibiting antibody was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process.