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

Mitsuhiro Machitani,Tomoko Yamaguchi,Kahori Shimizu,Fuminori Sakurai,Hiroyuki Mizuguchi,Kazufumi Katayama,Kenji Kawabata

doi:10.3390/pharmaceutics3030338

Mitsuhiro Machitani, Tomoko Yamaguchi + Show 5 more

Open Access

https://doi.org/10.3390/pharmaceutics3030338

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Abstract

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.

Highlights

The first-generation E1-deleted adenovirus (Ad) vector (FG-Ad vector) is one of the most promising vectors for gene therapy, as well as basic research due to its advantages as a gene delivery vehicle
We recently demonstrated that virus associated-RNAs (VA-RNAs) induce the production of type I IFN (IFN-α and IFN-β), but they do not induce the production of inflammatory cytokines (IL-6 and IL-12), in mouse embryonic fibroblasts (MEFs) and granulocyte-macrophage colony-stimulating factor-generated bone marrow-derived dendritic cells (GM-DCs) (Figure 2) [23]
We showed that IFN-β promoter stimulator-1 (IPS-1) is involved in VA-RNA-dependent IFN-β production in MEFs and is partially involved in type I IFN production in GM-DCs (Figure 2) [23]

Summary

Introduction

The first-generation E1-deleted adenovirus (Ad) vector (FG-Ad vector) is one of the most promising vectors for gene therapy, as well as basic research due to its advantages as a gene delivery vehicle. Application of FG-Ad vectors has been limited to local administration in most clinical trials of gene therapy, since the systemic administration of Ad vectors induces both adaptive and innate immune responses with its humoral and cell-mediated components [1,2]. In the FG-Ad vector, leaky expression of viral genes from the vector stimulates an immune response against Ad vector-transduced cells [3,4]. To reduce cell-mediated immune responses against viral gene products expressed in the transduced cells, “helper-dependent (HD)” or “gutted” Ad vectors have been developed. In this vector, all viral genes are deleted except the inverted terminal repeat (ITR) sequences at both ends and the packaging signal.

Ad vector-Mediated Innate Immune Responses

Signaling pathway leading to innate immune responses

Function of VA-RNAs and VA-RNA-mediated innate immune response

Development of an Ad vector lacking the expression of VA-RNAs

Findings

Conclusions