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., Civeira M.P., 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.
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