Strain-specific rate of shutdown of CMV enhancer activity in murine liver confirmed by use of persistent [E1(-), E2b(-)] adenoviral vectors

Virology
Ruth S EverettAndrea Amalfitano

Abstract

The systemic delivery of [E1(-)] adenoviral (Ad) vectors encoding a transgene results in efficient viral uptake and abundant transgene expression in the liver. However, [E1(-)]Ad vector persistence is transient due to cytotoxic T lymphocyte (CTL)-mediated loss of the Ad-infected cells. Our laboratory has previously demonstrated that additional modifications to the [E1(-)]Ad vector genome, by deletion of the Ad E2b genes, significantly decreased virus-genome-derived gene expression and simultaneously improved the long-term performance of the resultant [E1(-), E2b(-)]Ad vector. In this study, we confirmed that [E1(-), E2b(-)]Ad vector genomes could persist equally well in C57Bl/6 or Balb/c mouse hepatocytes. Despite vector genome persistence, we observed a strain-dependent variability in the duration of CMV enhancer/promoter-driven transgene expression in the liver. While Balb/c mice rapidly shut down [E1(-), E2b(-)]Ad-derived transgene expression, C57Bl/6 mice allowed for prolonged transgene expression. This occurred even when both strains were crossed into a severe combined immune-deficient background, demonstrating that host adaptive immune responses are not responsible for the phenomenon. Furthermore, differential methylation...Continue Reading

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Citations

Jan 29, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Sergey S SereginAndrea Amalfitano
Sep 29, 2009·Expert Opinion on Biological Therapy·Sergey S Seregin, Andrea Amalfitano
Dec 25, 2012·Translational Research : the Journal of Laboratory and Clinical Medicine·Tong Tang, H Kirk Hammond
Jun 27, 2006·Journal of Cellular and Molecular Medicine·Rachel Aronoff, C C H Petersen
Mar 13, 2015·Human Gene Therapy Methods·Xiufang PanDongsheng Duan
Nov 9, 2016·Molecular Therapy. Nucleic Acids·Alastair G KerrRichard Wade-Martins
Apr 12, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Paula Y P LamKam M Hui
Jan 20, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Alfred Y WangMark A Kay
Aug 9, 2007·Physiological Genomics·Frank Park

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