Document Detail


Differential type I interferon-dependent transgene silencing of helper-dependent adenoviral vs. adeno-associated viral vectors in vivo.
MedLine Citation:
PMID:  23319058     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Masataka Suzuki; Terry K Bertin; Geoffrey L Rogers; Racel G Cela; Irene Zolotukhin; Donna J Palmer; Philip Ng; Roland W Herzog; Brendan Lee
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-15
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-01     Completed Date:  2013-11-01     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  796-805     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / genetics*
Animals
Chromatin Immunoprecipitation
Genetic Vectors / genetics*
Helper Viruses / genetics
Histone Deacetylases / metabolism
Interferon Type I / genetics*
Liver / metabolism
Mice
Nuclear Proteins / metabolism
Transcription Factors / metabolism
Transgenes / genetics
Tumor Suppressor Proteins / metabolism
Grant Support
ID/Acronym/Agency:
K99HL098692/HL/NHLBI NIH HHS; P30 CA125123/CA/NCI NIH HHS; P50 CA126752/CA/NCI NIH HHS; R00 HL098692/HL/NHLBI NIH HHS; R01 AI051390/AI/NIAID NIH HHS; R01 DK067324/DK/NIDDK NIH HHS; R01AI51390/AI/NIAID NIH HHS; R01DK067324/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Interferon Type I; 0/Nuclear Proteins; 0/Pml protein, mouse; 0/Transcription Factors; 0/Tumor Suppressor Proteins; EC 3.5.1.98/Histone Deacetylases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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