Abstract
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.
Highlights
Each year influenza virus causes 3 to 5 million cases of severe illness and around half million deaths worldwide [1], with more than 200,000 hospitalizations and approximately 36,000 deaths in the United States alone [2,3]
influenza A virus (IAV) causes seasonal epidemics and periodic pandemics that result in significant morbidity and mortality worldwide
Broadly neutralizing antibodies targeting the conserved stalk region of IAV HA have been discovered. These antibodies are able to block the infection of many or even all IAV strains, and hold great promise as the generation of anti-flu treatment. Virus resistance to these antibodies has not been thoroughly studied despite the common view that broadly neutralizing stalk-binding antibodies are less permissive for mutational escape due to the functional importance of their highly conserved epitopes
Summary
Each year influenza virus causes 3 to 5 million cases of severe illness and around half million deaths worldwide [1], with more than 200,000 hospitalizations and approximately 36,000 deaths in the United States alone [2,3]. Influenza vaccines are available, they typically elicit strain-specific antibody responses and are ineffective against serologically distinct new viral variants. This is exemplified by the mismatch between the 2014 vaccine and the actual H3N2 IAV strain circulating during the 2014/15 winter season [5]. The current standards of treatment for influenza A infection are neuraminidase inhibitors such as oseltamivir phosphate (Tamiflu) and zanamivir (Relenza) that block the function of the viral neuraminidase (NA) protein, thereby blocking efficient viral release from infected cells Other antiviral drugs such as amantadine, an inhibitor of the viral ion channel M2, have been used. Antiviral resistance and vaccine mismatch can be attributed to the highly error-prone nature of the viral RNA-dependent RNA polymerase, which constantly introduces polymorphisms to viral proteins [8]
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