Plasmid DNA sequences present in conventional herpes simplex virus amplicon vectors cause rapid transgene silencing by forming inactive chromatin

Journal of Virology
Masataka SuzukiYoshinaga Saeki

Abstract

The herpes simplex virus (HSV)-based amplicon vector, a bacterial-viral-mammalian cell shuttle system, holds promise as a versatile gene delivery vehicle because of its large transgene capacity. However, amplicon-mediated transgene expression is often transient. We hypothesized that the presence of prokaryotic DNA sequences within the packaged vector genome can trigger transcriptional silencing of the entire vector sequence. To test this, we constructed a novel amplicon vector devoid of bacterial sequences (minicircle [MC] amplicon). Although the same dose of the minicircle amplicon vector in normal human fibroblasts resulted in an expression of luciferase approximately 20 times higher than that caused by the conventional amplicon vector, no significant difference was observed in copy numbers of luciferase DNA between MC amplicon- and control-transduced cells. Quantitative analyses of levels of luciferase mRNA revealed that differential expression of luciferase was controlled at the transcriptional level. Chromatin immunoprecipitation PCR analyses of several regions of vector genomes revealed that the bacterial sequences found in the conventional amplicon DNA were associated with an inactive form of chromatin immediately after ...Continue Reading

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Citations

Jul 9, 2013·Trends in Biotechnology·Pedro H Oliveira, Juergen Mairhofer
Aug 30, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Masataka SuzukiYoshinaga Saeki
Feb 19, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Masataka SuzukiYoshinaga Saeki
Jan 16, 2013·Molecular Therapy : the Journal of the American Society of Gene Therapy·Masataka SuzukiBrendan Lee
Apr 26, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Efren RiuMark A Kay
Jul 27, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Elise B PetersonWilliam J Bowers
Jul 27, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Masataka SuzukiYoshinaga Saeki
Feb 7, 2008·Molecular Therapy : the Journal of the American Society of Gene Therapy·Zhi-Ying ChenMark A Kay
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