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Pharmaceutics 2011, 3(3), 338-353; doi:10.3390/pharmaceutics3030338

Adenovirus Vector-Derived VA-RNA-Mediated Innate Immune Responses

1, 2, 1, 1, 1, 2,3 and 1,2,4,*
Received: 19 May 2011 / Revised: 27 June 2011 / Accepted: 5 July 2011 / Published: 11 July 2011
(This article belongs to the Special Issue Gene Therapy)
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The major limitation of the clinical use of replication-incompetent adenovirus (Ad) vectors is the interference by innate immune responses, including induction of inflammatory cytokines and interferons (IFN), following in vivo application of Ad vectors. Ad vector-induced production of inflammatory cytokines and IFNs also results in severe organ damage and efficient induction of acquired immune responses against Ad proteins and transgene products. Ad vector-induced innate immune responses are triggered by the recognition of Ad components by pattern recognition receptors (PRRs). In order to reduce the side effects by Ad vector-induced innate immune responses and to develop safer Ad vectors, it is crucial to clarify which PRRs and which Ad components are involved in Ad vector-induced innate immune responses. Our group previously demonstrated that myeloid differentiating factor 88 (MyD88) and toll-like receptor 9 (TLR9) play crucial roles in the Ad vector-induced inflammatory cytokine production in mouse bone marrow-derived dendritic cells. Furthermore, our group recently found that virus associated-RNAs (VA-RNAs), which are about 160 nucleotide-long non-coding small RNAs encoded in the Ad genome, are involved in IFN production through the IFN-β promoter stimulator-1 (IPS-1)-mediated signaling pathway following Ad vector transduction. The aim of this review is to highlight the Ad vector-induced innate immune responses following transduction, especially VA-RNA-mediated innate immune responses. Our findings on the mechanism of Ad vector-induced innate immune responses should make an important contribution to the development of safer Ad vectors, such as an Ad vector lacking expression of VA-RNAs.
Keywords: adenovirus vector; VA-RNA; gene therapy; innate immunity adenovirus vector; VA-RNA; gene therapy; innate immunity
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Machitani, M.; Yamaguchi, T.; Shimizu, K.; Sakurai, F.; Katayama, K.; Kawabata, K.; Mizuguchi, H. Adenovirus Vector-Derived VA-RNA-Mediated Innate Immune Responses. Pharmaceutics 2011, 3, 338-353.

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