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These mutator strains generate higher mutation frequencies than WT virus and are more sensitive to mutagenic treatments, and their purified polymerases present lower-fidelity profiles in an in vitro incorporation assay. Whereas these strains replicate with WT-like kinetics in tissue culture, in vivo infections reveal a strong correlation between mutation frequency and fitness. Variants with the highest mutation frequencies are less fit in vivo and fail to productively infect important target organs, such as the heart or pancreas. Furthermore, whereas WT virus is readily detectable in target organs 30 d after infection, some variants fail to successfully establish persistent infections. Our results show that, although mutator strains are sufficiently fit when grown in large population size, their fitness is greatly impacted when subjected to severe bottlenecking, which would occur during in vivo infection. The data indicate that, although RNA viruses have extreme mutation frequencies to maximize adaptability, nature has fine-tuned replication fidelity. Our work forges ground in showing that the mutability of RNA viruses does have an upper limit, where larger than natural genetic diversity is deleterious to virus survival.<\/jats:p>","DOI":"10.1073\/pnas.1204022109","type":"journal-article","created":{"date-parts":[[2012,8,1]],"date-time":"2012-08-01T21:01:03Z","timestamp":1343854863000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":131,"title":["Coxsackievirus B3 mutator strains are attenuated in vivo"],"prefix":"10.1073","volume":"109","author":[{"given":"Nina F.","family":"Gn\u00e4dig","sequence":"first","affiliation":[{"name":"Institut Pasteur, Centre National de la Recherche Scientifique Unit\u00e9 de Recherche Associ\u00e9e 3015, 75724 Paris Cedex 15, France;"},{"name":"University of Paris Diderot, Sorbonne Paris Cite, Cellule Pasteur, 75015 Paris, France; 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