title: Recombinant adenoviral vectors turn on the type I interferon system without inhibition of transgene expression and viral replication.
abstract: 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.
authors.affiliation: Center for Applied Medical Research, School of Medicine, and University Clinic, University of Navarra, Avenida Pio XII, 55, 31008 Pamplona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Huarte
authors.forename: Esther
authors.initials: E
authors.lastname: Larrea
authors.forename: Rubén
authors.initials: R
authors.lastname: Hernández-Alcoceba
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Arina
authors.forename: Iñigo
authors.initials: I
authors.lastname: Tirapu
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilicueta
authors.forename: Sandra
authors.initials: S
authors.lastname: Hervás-Stubbs
authors.forename: Sergia
authors.initials: S
authors.lastname: Bortolanza
authors.forename: José L
authors.initials: JL
authors.lastname: Pérez-Gracia
authors.forename: María P
authors.initials: MP
authors.lastname: Civeira
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: José I
authors.initials: JI
authors.lastname: Riezu-Boj
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000235:genetics* / Q000494:pharmacology; D016898:Interferon-alpha / Q000235:genetics / Q000494:pharmacology; D016899:Interferon-beta / Q000235:genetics / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D019076:Transgenes / Q000235:genetics*
chemical_list: D007370:Interferon Type I; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D016899:Interferon-beta; D013937:Thymidine Kinase