The TLR9-MyD88 pathway is critical for adaptive immune responses to adeno-associated virus gene therapy vectors in mice.

ABSTRACT: Recombinant adeno-associated viruses (AAVs) have been used widely for in vivo gene therapy. However, adaptive immune responses to AAV have posed a significant hurdle in clinical application of AAV vectors. Recent advances have suggested a crucial role for innate immunity in shaping adaptive immune responses. How AAV activates innate immunity, and thereby promotes AAV-targeted adaptive immune responses, remains unknown. Here we show that AAV activates mouse plasmacytoid DCs (pDCs) via TLR9 to produce type I IFNs. In vivo, the TLR9-MyD88 pathway was crucial to the activation of CD8+ T cell responses to both the transgene product and the AAV capsid, leading to loss of transgene expression and the generation of transgene product-specific and AAV-neutralizing antibodies. We further demonstrate

SUBMITTER: Zhu J 

PROVIDER: S-EPMC2719948 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature