Two Escape Mechanisms of Influenza A Virus to a Broadly Neutralizing Stalk-Binding Antibody

PLoS Pathogens

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