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Nat Microbiol. 2017 Jun 5;2:17088. doi: 10.1038/nmicrobiol.2017.88.

Attenuation of RNA viruses by redirecting their evolution in sequence space.

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Viral Populations and Pathogenesis Unit, Institut Pasteur, CNRS UMR 3569, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
International Group for Data Analysis, Institut Pasteur, C3BI, USR 3756 IP CNRS, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
Centre for Mathematical Sciences, Lund University, 22100 Lund, Sweden.
Sorbonne Paris Cité, Université Paris Diderot, Cellule Pasteur, 75013 Paris, France.
Unité d'Immunobiologie des Cellules Dendritiques, Institut Pasteur, Inserm 1223, 25 rue du Dr. Roux, 75724 Paris cedex 15, Paris, France.
Ecole doctorale Frontières du vivant, Université Paris Diderot, 75013 Paris, France.


RNA viruses pose serious threats to human health. Their success relies on their capacity to generate genetic variability and, consequently, on their adaptive potential. We describe a strategy to attenuate RNA viruses by altering their evolutionary potential. We rationally altered the genomes of Coxsackie B3 and influenza A viruses to redirect their evolutionary trajectories towards detrimental regions in sequence space. Specifically, viral genomes were engineered to harbour more serine and leucine codons with nonsense mutation targets: codons that could generate Stop mutations after a single nucleotide substitution. Indeed, these viruses generated more Stop mutations both in vitro and in vivo, accompanied by significant losses in viral fitness. In vivo, the viruses were attenuated, generated high levels of neutralizing antibodies and protected against lethal challenge. Our study demonstrates that cornering viruses in 'risky' areas of sequence space may be implemented as a broad-spectrum vaccine strategy against RNA viruses.

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