The complex and evolving story of T cell activation to AAV vector-encoded transgene products.
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.
Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Lauren E
LE
Mays
James M
JM
Wilson
D000818:Animals; D036022:Capsid Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes / Q000235:genetics / Q000276:immunology*
D036022:Capsid Proteins