Structural and functional definition of a vulnerable supersite on the hemagglutinin of highly pathogenic avian influenza A virus H5N1 Yanan Zuo Tsinghua University, Beijing, China
A large majority of protective neutralizing antibodies against highly pathogenic avian influenza (HPAI) A virus recognize the receptor binding site (RBS) on the globular head and the stem region of hemagglutinin (HA). We previously identified a major vulnerable site VS1 distinct from the RBS on the globular head of HPAI H5N1 HA through comprehensive analysis of multiple human protective antibodies. Here we report the crystal structures of additional two human H5N1 neutralizing antibodies 3C11 and AVFluIgG01 bound to the VS1. While significant overlap was found, the epitopes of 3C11 and AVFluIgG01 further extended beyond the original VS1, suggesting the existence of a vulnerable supersite away from the RBS. Mutagenesis studies further identified pivotal residues within the supersite critical for antibody binding and neutralization. These residues formed a unique “Y” shape surface on H5N1 HA and structurally conserved across H1N1 and H3N2 HA. Taken together, these results reveal the existence of an under-appreciated vulnerable supersite distinct from the RBS and the stem region of H5N1 HA, and future efforts in designing immunogens should take this particular site into consideration.
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