Structure-Guided Creation of an Anti-HA Stalk Antibody F11 Derivative That Neutralizes Both F11-Sensitive and -Resistant Influenza A(H1N1)pdm09 Viruses
Osamu Kotani,
Yasushi Suzuki,
Shinji Saito,
Akira Ainai,
Akira Ueno,
Takuya Hemmi,
Kaori Sano,
Koshiro Tabata,
Masaru Yokoyama,
Tadaki Suzuki,
Hideki Hasegawa,
Hironori Sato
Affiliations
Osamu Kotani
Center for Pathogen Genomics, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Yasushi Suzuki
Center for Influenza and Respiratory Virus Research, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Shinji Saito
Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Akira Ainai
Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Akira Ueno
Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Takuya Hemmi
Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Kaori Sano
Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Koshiro Tabata
Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Masaru Yokoyama
Center for Pathogen Genomics, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Tadaki Suzuki
Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Hideki Hasegawa
Center for Influenza and Respiratory Virus Research, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
Hironori Sato
Center for Pathogen Genomics, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
The stalk domain of influenza virus envelope glycoprotein hemagglutinin (HA) constitutes the axis connecting the head and transmembrane domains, and plays pivotal roles in conformational rearrangements of HA for virus infection. Here we characterized molecular interactions between the anti-HA stalk neutralization antibody F11 and influenza A(H1N1)pdm09 HA to understand the structural basis of the actions and modifications of this antibody. In silico structural analyses using a model of the trimeric HA ectodomain indicated that the F11 Fab fragment has physicochemical properties, allowing it to crosslink two HA monomers by binding to a region near the proteolytic cleavage site of the stalk domain. Interestingly, the F11 binding allosterically caused a marked suppression of the structural dynamics of the HA cleavage loop and flanking regions. Structure-guided mutagenesis of the F11 antibody revealed a critical residue in the F11 light chain for the F11-mediated neutralization. Finally, the mutagenesis led to identification of a unique F11 derivative that can neutralize both F11-sensitive and F11-resistant A(H1N1)pdm09 viruses. These results raise the possibility that F11 sterically and physically disturbs proteolytic cleavage of HA for the ordered conformational rearrangements and suggest that in silico guiding experiments can be useful to create anti-HA stalk antibodies with new phenotypes.
