Recombinant adenoviral vectors turn on the type I interferon system without inhibition of transgene expression and viral replication
Huarte E., Larrea E., Hernández-Alcoceba R., Alfaro C., Murillo O., Arina A., Tirapu I., Azpilicueta A., Hervás-Stubbs S., Bortolanza S., Pérez-Gracia J.L. [SP], Civeira M.P. [SP], Prieto J., Riezu-Boj J.I., Melero I.
Center for Applied Medical Research, School of Medicine, and University Clinic, University of Navarra, Avenida Pío XII, 55, 31008 Pamplona, Spain.
Magazine: Molecular Therapy
Date: Jul 1, 2006Hepatology Medical Oncology
Recombinant adenovirus administration gives rise to transgene-independent effects caused by the ability of the vector to activate innate immunity mechanisms.
We show that recombinant adenoviruses encoding reporter genes trigger IFN-alpha and IFN-beta transcription from both plasmacytoid and myeloid mouse dendritic cells. Interestingly, IFN-beta and IFN-alpha5 are the predominant transcribed type I IFN genes both in vitro and in vivo. In human peripheral blood leukocytes type I IFNs are induced by adenoviral vectors, with a preponderance of IFN-beta together with IFN-alpha1 and IFN-alpha5 subtypes. Accordingly, functional type I IFN is readily detected in serum samples from human cancer patients who have been treated intratumorally with a recombinant adenovirus encoding thymidine kinase. Despite inducing functional IFN-alpha release in both mice and humans, gene transfer by recombinant adenoviruses is not interfered with by type I IFNs either in vitro or in vivo. Moreover, IFN-alpha does not impair replication of wild-type adenovirus.
As a consequence, cancer gene therapy strategies with defective or replicative-competent adenoviruses are not expected to be hampered by the effect of the type I IFNs induced by the vector itself. However, type I IFN might modulate antitumor and antiadenoviral immune responses and thus influence the outcome of gene immunotherapy.
CITATION Mol Ther. 2006 Jul;14(1):129-38
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