title: Differential type I interferon-dependent transgene silencing of helper-dependent adenoviral vs. adeno-associated viral vectors in vivo.
abstract: We previously dissected the components of the innate immune response to Helper-dependent adenoviral vectors (HDAds) using genetic models, and demonstrated that multiple pattern recognition receptor signaling pathways contribute to this host response to HDAds in vivo. Based on analysis of cytokine expression profiles, type I interferon (IFN) mRNA is induced in host mouse livers at 1 hour post-injection. This type I IFN signaling amplifies cytokine expression in liver independent of the nature of vector DNA sequences after 3 hours post-injection. This type I IFN signaling in response to HDAds administration contributes to transcriptional silencing of both HDAd prokaryotic and eukaryotic DNA in liver. This silencing occurs early and is mediated by epigenetic modification as shown by in vivo chromatin immunoprecipitation (ChIP) with anti-histone deacetylase (HDAC) and promyelocytic leukemia protein (PML). In contrast, self-complementary adeno-associated viral vectors (scAAVs) showed significantly lower induction of type I IFN mRNA in liver compared to HDAds at both early and late time points. These results show that the type I IFN signaling dependent transgene silencing differs between AAV and HDAd vectors after liver-directed gene transfer.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,Texas 77030, USA.
authors: Masataka
authors: M
authors: Suzuki
authors: Terry K
authors: TK
authors: Bertin
authors: Geoffrey L
authors: GL
authors: Rogers
authors: Racel G
authors: RG
authors: Cela
authors: Irene
authors: I
authors: Zolotukhin
authors: Donna J
authors: DJ
authors: Palmer
authors: Philip
authors: P
authors: Ng
authors: Roland W
authors: RW
authors: Herzog
authors: Brendan
authors: B
authors: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D047369:Chromatin Immunoprecipitation; D005822:Genetic Vectors / Q000235:genetics*; D006378:Helper Viruses / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D009687:Nuclear Proteins; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D006655:Histone Deacetylases