Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2006-08

AUTHORS

Luk H Vandenberghe, Lili Wang, Suryanarayan Somanathan, Yan Zhi, Joanita Figueredo, Roberto Calcedo, Julio Sanmiguel, Ravi A Desai, Christopher S Chen, Julie Johnston, Rebecca L Grant, Guangping Gao, James M Wilson

ABSTRACT

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 B. 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 clades 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). 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. More... »

PAGES

967-971

Journal

TITLE

Nature Medicine

ISSUE

8

VOLUME

12

Author Affiliations

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm1445

DOI

http://dx.doi.org/10.1038/nm1445

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1002626629

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/16845388


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