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Publication Abstract from PubMed

Human infection with highly pathogenic avian influenza A viruses lead to cause severe diseases and fatalities. We previously identified a potent and broad-neutralizing antibody (bnAb), 13D4, against the H5N1 virus. Here, we report the co-crystal structure of 13D4 in complex with the hemagglutinin of A/Vietnam/1194/2004 (H5N1). We show that the heavy chain complementarity determining region 3 (HCDR3) of 13D4 confers H5N1 broad yet specific neutralization against H5N1, undergoing conformational rearrangement to bind to the receptor-binding site (RBS). Further, we show that mutating four critical residues within the RBS-Trp153, Lys156, Lys193, Leu194-disrupts the binding between 13D4 and HA. Viruses bearing Asn193 instead of Lys/Arg can evade 13D4 neutralization, indicating that Lys193 polymorphism might be, at least in part, involved in the antigenicity of recent H5 genotypes (such as H5N6 and H5N8) distinguished from H5N1. BnAb 13D4 may offers a template for therapeutic RBS-inhibitor design and serve as an indicator of antigenic change of current H5 viruses.IMPORTANCE The infection of highly pathogenic avian influenza A virus remains a threat for public health. Our broad-neutralizing antibody, 13D4, is capable of neutralizing all representative H5N1 viruses and protecting mice against lethal challenge. Structural analysis revealed that 13D4 uses the heavy chain complementarity determining region 3 (HCDR3) to fit to receptor binding site (RBS) via conformational rearrangement. Four conserved residues within the RBS are critical for the broad potency of 13D4. Importantly, polymorphism of Lys193 on RBS may be associated with the antigenicity shift from H5N1 to other new emerging viruses, such as H5N6 and H5N8. Our findings may pave a way for highly pathogenic avian influenza vaccine development and therapeutic RBS-inhibitor design.

Structural Basis for the Broad, Antibody-Mediated Neutralization of H5N1 Influenza Virus.,Lin Q, Li T, Chen Y, Lau SY, Wei M, Zhang Y, Zhang Z, Yao Q, Li J, Li Z, Wang D, Zheng Q, Yu H, Gu Y, Zhang J, Chen H, Li S, Xia N J Virol. 2018 Jun 20. pii: JVI.00547-18. doi: 10.1128/JVI.00547-18. PMID:29925655^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.