Original Article | Published:

Adenovirus-mediated artificial MicroRNAs targeting matrix or nucleoprotein genes protect mice against lethal influenza virus challenge

Gene Therapy volume 22, pages 653662 (2015) | Download Citation

Abstract

Influenza virus (IV) infection is a major public health problem, causing millions of cases of severe illness and as many as 500 000 deaths each year worldwide. Given the limitations of current prevention or treatment of acute influenza, novel therapies are needed. RNA interference (RNAi) through microRNAs (miRNA) is an emerging technology that can suppress virus replication in vitro and in vivo. Here, we describe a novel strategy for the treatment of infuenza based on RNAi delivered by a replication-defective adenovirus (Ad) vector, derived from chimpanzee serotype 68 (AdC68). Our results showed that artificial miRNAs (amiRNAs) specifically targeting conserved regions of the IV genome could effectively inhibit virus replication in human embryonic kidney 293 cells. Moreover, our results demonstrated that prophylactic treatment with AdC68 expressing amiRNAs directed against M1, M2 or nucleoprotein genes of IV completely protected mice from homologous A/PR8 virus challenge and partially protected the mice from heterologous influenza A virus strains such as H9N2 and H5N1. Collectively, our data demonstrate that amiRNAs targeting the conserved regions of influenza A virus delivered by Ad vectors should be pursued as a novel strategy for prophylaxis of IV infection in humans and animals.

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Acknowledgements

This work was supported by grants from Natural Science Foundation of China (31170871, 31370929 and 31200698), ‘Knowledge Innovation Program’ and ‘100 Talent Program’ from Chinese Academy of Sciences, the Shanghai Pasteur Foundation, China 863 program (2014AA021003). Partial support was also provided by Postdoctoral Science Foundation of China (2013T60470 and 2013M541559) and Postdoctoral Science Foundation of Shanghai Municipality, China (12R21416900). We gratefully acknowledge Jiawei Wang, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, for his generous assistance and reagents.

Author information

Author notes

    • H Zhang
    •  & X Tang

    These authors contributed equally to this work.

Affiliations

  1. Vaccine Research Center, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

    • H Zhang
    • , X Tang
    • , C Zhu
    • , Y Song
    • , J Yin
    •  & D Zhou
  2. Shanghai Public Health Clinical Center, the Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai, China

    • J Xu
  3. The Wistar Institute, Philadelphia, PA, USA

    • H C J Ertl

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to D Zhou.

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DOI

https://doi.org/10.1038/gt.2015.31

Supplementary Information accompanies this paper on Gene Therapy website (http://www.nature.com/gt)

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