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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.

SUBMITTER: Hui DJ

PROVIDER: S-EPMC4588448 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes.

Hui Daniel J DJ Edmonson Shyrie C SC Podsakoff Gregory M GM Pien Gary C GC Ivanciu Lacramioara L Camire Rodney M RM Ertl Hildegund H Mingozzi Federico F High Katherine A KA Basner-Tschakarjan Etiena E

Molecular therapy. Methods & clinical development 20150930

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 ...[more]

PMID: 26445723

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AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes.

Publications

AAV capsid CD8+ T-cell epitopes are highly conserved across AAV serotypes.

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