Nature Medicine
- 12, 967 - 971 (2006)
Published online: 16 July 2006; | doi:10.1038/nm1445
Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsidLuk H Vandenberghe1, 2, 4, Lili Wang1, 4, Suryanarayan Somanathan1, Yan Zhi1, Joanita Figueredo1, Roberto Calcedo1, Julio Sanmiguel1, Ravi A Desai3, Christopher S Chen3, Julie Johnston1, Rebecca L Grant1, Guangping Gao1 & James M Wilson11
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 125 S. 31st Street, Philadelphia, Pennsylvania 19104, USA. 2
Molecular Medicine, Katholieke Universiteit Leuven, Kapucijnenvoer 33, B-3000 Leuven, Belgium. 3
Department of Bioengineering, University of Pennsylvania School of Engineering and Applied Science, 120 Hayden Hall, 3320 Smith Walk, Philadelphia, Pennsylvania 19104, USA. 4
These authors contributed equally to this work.
Correspondence should be addressed to James M Wilson wilsonjm@mail.med.upenn.edu Activation of T cells to the capsid of adeno-associated virus (AAV) serotype 2 vectors has been implicated in liver toxicity in a recent human gene therapy trial of hemophilia B1. To further investigate this kind of toxicity, we evaluated T-cell responses to AAV capsids after intramuscular injection of vectors into mice and nonhuman primates. High levels of T cells specific to capsids of vectors based on AAV2 and a phylogenetically related AAV variant were detected. Vectors from other AAV clades2 such as AAV8 (ref. 3), however, did not lead to activation of capsid-specific T cells. Through the generation of AAV2-AAV8 hybrids and the creation of site-directed mutations, we mapped the domain that directs the activation of T cells to the RXXR motif on VP3, which was previously shown to confer binding of the virion to heparan sulfate proteoglycan (HSPG)4,
5,
6. Evaluation of natural and engineered AAV variants showed direct correlations between heparin binding, uptake into human dendritic cells (DCs) and activation of capsid-specific T cells. The role of heparin binding in the activation of CD8+ T cells may be useful in modulating the immunogenicity of antigens and improving the safety profile of existing AAV vectors for gene therapy.
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