Recombinant adenoviral vectors turn on the type I interferon system without inhibition of transgene expression and viral replication.
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.
Huarte
Eduardo
E
Center for Applied Medical Research, School of Medicine, and University Clinic, University of Navarra, Avenida Pio XII, 55, 31008 Pamplona, Spain.
Larrea
Esther
E
Hernández-Alcoceba
Rubén
R
Alfaro
Carlos
C
Murillo
Oihana
O
Arina
Ainhoa
A
Tirapu
Iñigo
I
Azpilicueta
Arantza
A
Hervás-Stubbs
Sandra
S
Bortolanza
Sergia
S
Pérez-Gracia
José L
JL
Civeira
María P
MP
Prieto
Jesús
J
Riezu-Boj
José I
JI
Melero
Ignacio
I
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*
D007370:Interferon Type I; D016898:Interferon-alpha; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D016899:Interferon-beta; D013937:Thymidine Kinase