title: AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes.
abstract: 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.
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hui
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA ; Howard Hughes Medical Institute , Philadelphia, Pennsylvania, USA.
authors.forename: Shyrie C
authors.initials: SC
authors.lastname: Edmonson
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Podsakoff
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Pien
authors.affiliation: 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.
authors.forename: Lacramioara
authors.initials: L
authors.lastname: Ivanciu
authors.affiliation: Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: Rodney M
authors.initials: RM
authors.lastname: Camire
authors.affiliation: Wistar Institute , Philadelphia, Pennsylvania, USA.
authors.forename: Hildegund
authors.initials: H
authors.lastname: Ertl
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Mingozzi
authors.affiliation: 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.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: High
authors.affiliation: The Children's Hospital of Philadelphia, Division of Hematology , Philadelphia, Pennsylvania, USA.
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan