AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes.
Daniel J Hui, Shyrie C Edmonson, Gregory M Podsakoff, Gary C Pien, Lacramioara Ivanciu, Rodney M Camire, Hildegund Ertl, Federico Mingozzi, Katherine A High, Etiena Basner-Tschakarjan
Author Information
Daniel J Hui: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
Shyrie C Edmonson: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA ; Howard Hughes Medical Institute , Philadelphia, Pennsylvania, USA.
Gregory M Podsakoff: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
Gary C Pien: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
Lacramioara Ivanciu: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA ; Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
Rodney M Camire: Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
Hildegund Ertl: Wistar Institute , Philadelphia, Pennsylvania, USA.
Federico Mingozzi: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
Katherine A High: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA ; Howard Hughes Medical Institute , Philadelphia, Pennsylvania, USA ; Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
Etiena Basner-Tschakarjan: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immune responses against the vector capsid can present an obstacle to sustained transgene expression due to the activation and expansion of capsid-specific T cells. The limited number of peripheral blood mononuclear cells (PBMCs) obtained from samples within clinical trials allows for little more than monitoring of T-cell responses. We were able to identify immunodominant major histocompatibility complex (MHC) class I epitopes for common human leukocyte antigen (HLA) types by using spleens isolated from subjects undergoing splenectomy for non-malignant indications as a source of large numbers of lymphocytes and restimulating them with single AAV capsid peptides in vitro. Further experiments confirmed that these epitopes are naturally processed and functionally relevant. The design of more effective and less immunogenic AAV vectors, and precise immune monitoring of vector-infused subjects, are facilitated by these findings.
