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

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

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1
Department of Pathology and Laboratory Medicine, Division of Transfusion Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Abstract

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.

PMID:
21119617
PMCID:
PMC3017457
DOI:
10.1038/mt.2010.250
[Indexed for MEDLINE]
Free PMC Article

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