Virus attenuation by genome-scale changes in codon pair bias.
As a result of the redundancy of the genetic code, adjacent pairs of amino acids can be encoded by as many as 36 different pairs of synonymous codons. A species-specific "codon pair bias" provides that some synonymous codon pairs are used more or less frequently than statistically predicted. We synthesized de novo large DNA molecules using hundreds of over-or underrepresented synonymous codon pairs to encode the poliovirus capsid protein. Underrepresented codon pairs caused decreased rates of protein translation, and polioviruses containing such amino acid-independent changes were attenuated in mice. Polioviruses thus customized were used to immunize mice and provided protective immunity after challenge. This "death by a thousand cuts" strategy could be generally applicable to attenuating many kinds of viruses.
Coleman
J Robert
JR
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA.
Papamichail
Dimitris
D
Skiena
Steven
S
Futcher
Bruce
B
Wimmer
Eckard
E
Mueller
Steffen
S
D000465:Algorithms; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D036022:Capsid Proteins / Q000235:genetics*; D003001:Cloning, Molecular; D003062:Codon; D003588:Cytopathogenic Effect, Viral; D016679:Genome, Viral; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D011051:Poliomyelitis / Q000276:immunology / Q000821:virology; D017955:Poliovirus / Q000235:genetics* / Q000254:growth & development / Q000276:immunology / Q000472:pathogenicity*; D023321:Poliovirus Vaccines / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D010948:Viral Plaque Assay; D014774:Virulence
D000914:Antibodies, Viral; D036022:Capsid Proteins; D003062:Codon; D023321:Poliovirus Vaccines; D014613:Vaccines, Attenuated