Neutralization and infection-enhancement epitopes of influenza A virus hemagglutinin.

We studied 18 mAb specific for the H3 hemagglutinin (HA) to analyze the relationships between neutralizing and infection-enhancing epitopes on the influenza HA. The mAb could be separated into three groups based on their neutralization (N) and enhancement (E) activity in assays with the prototype virus; group I (N+E+), group II (N+E-) and group III (N +/- E+). A representative mAb from each group was analyzed for its effect on the infectivity of a group of escape mutants, selected with mAb to three sites on the H3 HA, and wild-type H3 viruses to define the relationship between neutralizing epitopes and infection-enhancing epitopes. A group I mAb (N+E+), which recognized site A on the HA, neutralized virus infection at high concentrations of antibody and enhanced virus infection at low concentrations. A group II mAb (N+E-), which recognized site B, had high neutralizing but no enhancing activity. The failure of this mAb to enhance virus uptake was a result of the inability of the Fc portion of virus-mAb complexes to bind to Fc receptor. The addition of anti-murine IgG as a second antibody to these virus-mAb complexes augmented virus uptake. A group III mAb (N +/- E+), which recognized site C, had enhancing but little neutralizing activity. This is the first definition of distinct epitopes that induce neutralizing and/or enhancing mAb.