This article is part of the Research Topic Immune responses to AAV vectors, from bench to bedside


Front. Immunol., 23 July 2014 | doi: 10.3389/fimmu.2014.00350

Cell-mediated immunity to AAV vectors, evolving concepts and potential solutions

  • 1Department of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
  • 2University Pierre and Marie Curie, Paris, France
  • 3Genethon, Evry, France

Adeno-associated virus (AAV) vectors are one of the most efficient in vivo gene delivery platforms. Over the past decade, clinical trials of AAV vector-mediated gene transfer led to some of the most exciting results in the field of gene therapy and, recently, to the market approval of an AAV-based drug in Europe. With clinical development, however, it became obvious that the host immune system represents an important obstacle to successful gene transfer with AAV vectors. In this review article, we will discuss the issue of cytotoxic T cell responses directed against the AAV capsid encountered on human studies. While over the past several years the field has acquired a tremendous amount of information on the interactions of AAV vectors with the immune system, a lot of questions are still unanswered. Novel concepts are emerging, such as the relationship between the total capsid dose and the T cell-mediated clearance of transduced cells, the potential role of innate immunity in vector immunogenicity highlighted in preclinical studies, and the cross talk between regulatory and effector T cells in the determination of the outcome of gene transfer. There is still a lot to learn about immune responses in AAV gene transfer, for example, it is not well understood what are the determinants of the kinetics of activation of T cells in response to vector administration, why not all subjects develop detrimental T cell responses following gene transfer, and whether the intervention strategies currently in use to block T cell-mediated clearance of transduced cells will be safe and effective for all gene therapy indications. Results from novel preclinical models and clinical studies will help to address these points and to reach the important goal of developing safe and effective gene therapy protocols to treat human diseases.

Keywords: AAV vectors, T cell responses, gene therapy, immunogenicity, immune modulation

Citation: Basner-Tschakarjan E and Mingozzi F (2014) Cell-mediated immunity to AAV vectors, evolving concepts and potential solutions. Front. Immunol. 5:350. doi: 10.3389/fimmu.2014.00350

Received: 08 April 2014; Accepted: 08 July 2014;
Published online: 23 July 2014.

Edited by:

Hildegard Büning, University of Cologne, Germany

Reviewed by:

Roland W. Herzog, University of Florida, USA
Hildegard Büning, University of Cologne, Germany

Copyright: © 2014 Basner-Tschakarjan and Mingozzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Etiena Basner-Tschakarjan, The Children’s Hospital of Philadelphia, 3501 Civic Center Blvd Suite 5400, Philadelphia, PA 19104, USA e-mail:;
Federico Mingozzi, Genethon, 1 bis rue de l’Internationale, Evry 91000, France e-mail:

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