The complex and evolving story of T cell activation to AAV vector-encoded transgene products

Mol Ther. 2011 Jan;19(1):16-27. doi: 10.1038/mt.2010.250. Epub 2010 Nov 30.


Original reports of adeno-associated virus (AAV) vector-mediated gene transfer to the muscle resulted in high-level β-galactosidase (β-gal) expression and the promise of a viral vector that was largely nonimmunogenic. Subsequent attempts to utilize these vectors for genetic vaccination, however, demonstrated that it was possible to activate cellular and humoral immunity to AAV-encoded antigens. These findings fueled years of investigation into factors impacting the immunogenicity of recombinant AAV-mediated gene delivery, including route of administration, dose, host species, capsid serotype, and transgene product. In cases where AAV vectors could avoid transgene-directed immunity, it became clear that mechanisms of tolerance were at work, varying between ignorance, anergy/deletion, or active suppression. Here, we follow the field of AAV gene therapy from inception, as investigators have worked to understand the delicate balance between AAV-mediated tolerance and the activation of immunity. This review discusses our current appreciation of AAV vector immunology, with a specific focus on the transgene-specific T cell response.

Publication types

  • Review

MeSH terms

  • Animals
  • Capsid Proteins / administration & dosage
  • Capsid Proteins / genetics
  • Capsid Proteins / immunology*
  • Dependovirus / genetics
  • Dependovirus / immunology*
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Genetic Vectors / immunology*
  • Humans
  • Immune Tolerance / immunology
  • Lymphocyte Activation / immunology
  • T-Lymphocytes / immunology*
  • Transgenes / genetics
  • Transgenes / immunology*


  • Capsid Proteins