Directed evolution of adeno-associated virus to an infectious respiratory virus

Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3865-70. doi: 10.1073/pnas.0813365106. Epub 2009 Feb 23.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capsid / chemistry
  • Cell Line
  • Cell Polarity
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis / virology
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Dependovirus / genetics*
  • Directed Molecular Evolution*
  • Epithelial Cells / pathology
  • Epithelial Cells / virology
  • Gene Library
  • Genetic Vectors / genetics
  • Humans
  • Models, Molecular
  • Mutation / genetics
  • N-Acetylneuraminic Acid / metabolism
  • Parvoviridae Infections / virology*
  • Phenotype
  • Selection, Genetic
  • Transduction, Genetic
  • Virus Attachment


  • Cystic Fibrosis Transmembrane Conductance Regulator
  • N-Acetylneuraminic Acid