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Expression of an engineered soluble coxsackievirus and adenovirus receptor by a dimeric AAV9 vector inhibits adenovirus infection in mice

Gene Therapy volume 22, pages 458–466 (2015)Cite this article

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Abstract

Immunosuppressed (IS) patients, such as recipients of hematopoietic stem cell transplantation, occasionally develop severe and fatal adenovirus (Ad) infections. Here, we analyzed the potential of a virus receptor trap based on a soluble coxsackievirus and Ad receptor (sCAR) for inhibition of Ad infection. In vitro, a dimeric fusion protein, sCAR-Fc, consisting of the extracellular domain of CAR and the Fc portion of human IgG1 and a monomeric sCAR lacking the Fc domain, were expressed in cell culture. More sCAR was secreted into the cell culture supernatant than sCAR-Fc, but it had lower Ad neutralization activity than sCAR-Fc. Further investigations showed that sCAR-Fc reduced the Ad infection by a 100-fold and Ad-induced cytotoxicity by ~20-fold. Not only was Ad infection inhibited by sCAR-Fc applied prior to infection, it also inhibited infection when used to treat ongoing Ad infection. In vivo, sCAR-Fc was delivered to IS mice by an AAV9 vector, resulting in persistent and high (>40 μg ml−1) sCAR-Fc serum levels. The sCAR-Fc serum concentration was sufficient to significantly inhibit hepatic and cardiac wild-type Ad5 infection. Treatment with sCAR-Fc did not induce side effects. Thus, sCAR-Fc virus receptor trap may be a promising novel therapeutic for treatment of Ad infections.

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Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (Grants FE785/2-2, FE785, 3-1, FE785/4-1 to HF, Ku 1436/6-1 to JK) and by a doctoral studies grant to CR from the Sonnenfeld Stiftung. We thank Erik Wade for critical reading of the manuscript and helpful comments and Xiaomin Wang for helpful assistance with Wt-Ad5 preparation.

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Author notes

  1. S Pinkert and H Fechner: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Gustav-Meyer-Allee 25, Berlin, Germany

    C Röger, T Pozzuto, J Kurreck, S Pinkert & H Fechner

  2. Department of Vetrinary Medicine, Institute of Veterinary Pathology, Freie Universität Berlin, Robert-von-Ostertag-Strasse 15, Berlin, Germany

    R Klopfleisch

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  1. C Röger
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Correspondence to H Fechner.

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Röger, C., Pozzuto, T., Klopfleisch, R. et al. Expression of an engineered soluble coxsackievirus and adenovirus receptor by a dimeric AAV9 vector inhibits adenovirus infection in mice. Gene Ther 22, 458–466 (2015). https://doi.org/10.1038/gt.2015.19

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