Directed evolution of adeno-associated virus to an infectious respiratory virus.
Respiratory viruses evolve to maintain infectivity levels that permit spread yet prevent host and virus extinction, resulting in surprisingly low infection rates. Respiratory viruses harnessed as gene therapy vectors have illustrated this limitation. We used directed evolution in an organotypic human airway model to generate a highly infectious adeno-associated virus. This virus mediated gene transfer more than 100-fold better than parental strains and corrected the cystic fibrosis epithelial Cl(-) transport defect. Thus, under appropriate selective pressures, viruses can evolve to be more infectious than observed in nature, a finding that holds significant implications for designing vectors for gene therapy and for understanding emerging pathogens.
Excoffon
Katherine J D A
KJ
Department of Internal Medicine, University of Iowa, 440 EMRB, Iowa City, IA 52241, USA.
Koerber
James T
JT
Dickey
David D
DD
Murtha
Matthew
M
Keshavjee
Shaf
S
Kaspar
Brian K
BK
Zabner
Joseph
J
Schaffer
David V
DV
D000818:Animals; D002213:Capsid / Q000737:chemistry; D002460:Cell Line; D016764:Cell Polarity; D003550:Cystic Fibrosis / Q000473:pathology / Q000821:virology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D019020:Directed Molecular Evolution; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology; D015723:Gene Library; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D010322:Parvoviridae Infections / Q000821:virology*; D010641:Phenotype; D012641:Selection, Genetic; D014161:Transduction, Genetic; D053585:Virus Attachment
D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019158:N-Acetylneuraminic Acid