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Journal of Virology, April 2007, p. 3170-3180, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02192-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways{triangledown}

Jiangao Zhu,1 Xiaopei Huang,1 and Yiping Yang1,2*

Department of Medicine, Division of Medical Oncology,1 Department of Immunology, Duke University Medical Center, Box 3502, Durham, North Carolina 277102

Received 5 October 2006/ Accepted 9 January 2007

Recombinant adenoviral vectors have been widely used for gene therapy applications and as vaccine vehicles for treating infectious diseases such as human immunodeficiency virus disease. The innate immune response to adenoviruses represents the most significant hurdle in clinical application of adenoviral vectors for gene therapy, but it is an attractive feature for vaccine development. How adenovirus activates innate immunity remains largely unknown. Here we showed that adenovirus elicited innate immune response through the induction of high levels of type I interferons (IFNs) by both plasmacytoid dendritic cells (pDCs) and non-pDCs such as conventional DCs and macrophages. The innate immune recognition of adenovirus by pDCs was mediated by Toll-like receptor 9 (TLR9) and was dependent on MyD88, whereas that by non-pDCs was TLR independent through cytosolic sensing of adenoviral DNA. Furthermore, type I IFNs were pivotal in innate and adaptive immune responses to adenovirus in vivo, and type I IFN blockade diminished immune responses, resulting in more stable transgene expression and reduction of inflammation. These findings indicate that adenovirus activates innate immunity by its DNA through TLR-dependent and -independent pathways in a cell type-specific fashion, and they highlight a critical role for type I IFNs in innate and adaptive immune responses to adenoviral vectors. Our results that suggest strategies to interfere with type I IFN pathway may improve the outcome of adenovirus-mediated gene therapy, whereas approaches to activate the type I IFN pathway may enhance vaccine potency.

* Corresponding author. Mailing address: Department of Medicine, Duke University Medical Center, Box 3502, Durham, NC 27710. Phone: (919) 668-0932. Fax: (919) 684-9594. E-mail: yang0029{at}mc.duke.edu.

{triangledown} Published ahead of print on 17 January 2007.

Journal of Virology, April 2007, p. 3170-3180, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02192-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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