PLoS Pathogens | |
Two Escape Mechanisms of Influenza A Virus to a Broadly Neutralizing Stalk-Binding Antibody | |
Olga Li1  Haiyin Chen-Harris1  Min Xu1  Elizabeth Luis2  Jacqueline McBride3  Michael Lawrence3  Lee R. Swem4  Ning Chai4  Patrick Lupardus4  Mike Reichelt5  Summer Park6  Thomas D. Wu7  Ashley Fouts8  Man-Wah Tan8  | |
[1] Bioinformatics & Computational Biology Department, Genentech, South San Francisco, California, United States of America;Cancer Immunology Department, Genentech, South San Francisco, California, United States of America;Development Sciences Department, Genentech, South San Francisco, California, United States of America;Infectious Diseases Department, Genentech, South San Francisco, California, United States of America;Pathology Department, Genentech, South San Francisco, California, United States of America;Protein Chemistry Department, Genentech, South San Francisco, California, United States of America;Structural Biology Department, Genentech, South San Francisco, California, United States of America;Translational Immunology Department, Genentech, South San Francisco, California, United States of America | |
关键词: Antibodies; Membrane fusion; Cell fusion; Influenza A virus; Microbial mutation; Flow cytometry; Serine proteases; HeLa cells; | |
DOI : 10.1371/journal.ppat.1005702 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
Broadly neutralizing antibodies targeting the stalk region of influenza A virus (IAV) hemagglutinin (HA) are effective in blocking virus infection both in vitro and in vivo. The highly conserved epitopes recognized by these antibodies are critical for the membrane fusion function of HA and therefore less likely to be permissive for virus mutational escape. Here we report three resistant viruses of the A/Perth/16/2009 strain that were selected in the presence of a broadly neutralizing stalk-binding antibody. The three resistant viruses harbor three different mutations in the HA stalk: (1) Gln387Lys; (2) Asp391Tyr; (3) Asp391Gly. The Gln387Lys mutation completely abolishes binding of the antibody to the HA stalk epitope. The other two mutations, Asp391Tyr and Asp391Gly, do not affect antibody binding at neutral pH and only slightly reduce binding at low pH. Interestingly, they enhance the fusion ability of the HA, representing a novel mechanism that allows productive membrane fusion even in the presence of antibody and hence virus escape from antibody neutralization. Therefore, these mutations illustrate two different resistance mechanisms used by IAV to escape broadly neutralizing stalk-binding antibodies. Compared to the wild type virus, the resistant viruses release fewer progeny viral particles during replication and are more sensitive to Tamiflu, suggesting reduced viral fitness.
【 授权许可】
CC BY
【 预 览 】
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RO201902016451428ZK.pdf | 9628KB | download |