Prevalent phenotypic mutation impairs binding of broadly neutralizing antibodies to influenza hemagglutinin

Mistakes during protein synthesis, such as transcription errors, occur often and lead to non-inheritable amino acid replacements generally known as phenotypic mutations. We recently used a consensus approach in high-throughput sequencing to determine the error landscape for influenza-hemagglutinin mRNA. We found single-site errors to occur with widely different frequencies. Here we show that the most prevalent transcription error encodes a phenotypic mutation that impairs binding of broadly neutralizing antibodies. The error occurs in 0.2-0.5% of mRNA molecules and, consequently, many virions will expose hemagglutinin variants bearing the encoded amino acid replacement. Our results point to a mechanism of antibody evasion, akin to programmed recoding, in which evading mutations are encoded by transcription errors promoted by inheritable RNA sequence/structure patterns.