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Influence of chimeric human-bovine fibers on adenoviral uptake by liver cells and the antiviral immune response

Gene Therapy volume 17, pages 880–891 (2010)Cite this article

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Abstract

Human adenoviruses (HAdV) are widely used for in vitro and in vivo gene transfer. Viral hepatotropism, inflammatory responses and neutralization by pre-existing antibodies (NAbs) are obstacles for clinical applications of HAdV vectors. Although the multifactorial events leading to innate HAdV toxicity are far from being elucidated, there is a consensus that the majority of intravenously injected-HAdV vectors is sequestered by Kuppfer cells, probably independently of coagulation factors. In this study, we show that the adenoviral-associated humoral and innate cytokine immune responses are significantly reduced when HAdV-5 vector carrying human bovine chimeric fibers (HAdV-5-F2/BAdV-4) is intravenously injected into mice. Fiber pseudotyping modified its interaction with blood coagulation factors, as FIX and FX no longer mediate the infection of liver cells by HAdV-5-F2/BAdV-4. As a consequence, at early time points post-infection, several cytokines and chemokines (IFN-γ, IL-6, IP-10, MCP-1, RANTES and MP1β) were found to be present at lower levels in the plasma of mice that had been intravenously injected with HAdV-5-F2/BAdV-4 compared with mice injected with the parental vector HAdV-5. Moreover, genetic modification of the fiber allowed HAdV-5-F2/BAdV-4 to partially escape neutralization by NAbs.

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Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale, Institut de Recherches sur le Cancer de Lille, Ligue Nationale contre le Cancer, Comité du Nord (J.C. D’Halluin, M. Colin) and Comité de l’Aisne (J.C. D’Halluin), the Région Nord-Pas de Calais, the Lille University Hospital (CHR; S. Rogée, E. Grellier), and the French Foundation against Cystic Fibrosis ‘Vaincre la Mucoviscidose’ (VLM; S.S. Hong, P. Boulanger). We are grateful to B. Hennache, at the Biochemistry Units of CHR of Lille, for performing the ALT assays and to A Bauters, at the Hematology transfusion units of the CHR of Lille for performing the CTs assays. We extend our thanks to IMPRT-114 for the platform facilities (cell sorting, confocal and electron microscopy and molecular interaction analyses), and many thanks to Pierre-Marie Danzé and Anne-Sophie Drucker for helpful discussions.

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Author notes

  1. S Rogée

    Present address: 8Present address: Institut Cochin, 22 rue Méchain, 75014 Paris.,

  2. S Rogée and E Grellier: First authors contributed equally.

  3. J C D'Halluin and M Colin: Last authors contributed equally.

Authors and Affiliations

  1. Inserm (Institut National de la Santé et de la Recherche Médicale), U837, Place de Verdun, Lille, France

    S Rogée, E Grellier, C Bernard, N Jouy, A Loyens & J C Beauvillain

  2. University Lille Nord de France, Lille, France

    S Rogée, E Grellier, C Bernard, N Jouy, A Loyens, J C Beauvillain, B Quesnel, J C D'Halluin & M Colin

  3. Institut de Recherches sur le Cancer de Lille, Place de Verdun, Lille, France

    S Rogée, E Grellier, C Bernard, N Jouy, B Quesnel, J C D'Halluin & M Colin

  4. UDSL (Université Droit et Santé de Lille), Faculté de Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique, Centre de Recherche Jean-Pierre Aubert, 1 Place de Verdun, Lille, France

    A Loyens, B Quesnel & M Colin

  5. Institut de Biologie Structurale (UMR5075: CNRS/CEA/UJF) 41, rue Jules Horowitz 38027 Grenoble, France

    P Fender

  6. Université Lyon 1 and UMR INRA-754, Rétrovirus & Pathologie Comparée, Lyon Cedex, France

    S Corjon, S S Hong & P Boulanger

  7. Service des Maladies du Sang, Centre Hospitalier et Universitaire de Lille, Rue Polonovski, Lille, France

    B Quesnel

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  1. S Rogée
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Correspondence to M Colin.

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Rogée, S., Grellier, E., Bernard, C. et al. Influence of chimeric human-bovine fibers on adenoviral uptake by liver cells and the antiviral immune response. Gene Ther 17, 880–891 (2010). https://doi.org/10.1038/gt.2010.37

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