Department of Molecular and Human Genetics, Baylor College of Medicine, Houston,Texas 77030, USA.
Mol Ther. 2013 Apr;21(4):796-805. doi: 10.1038/mt.2012.277. Epub 2013 Jan 15.
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.
我们之前使用遗传模型对 Helper-dependent 腺病毒载体 (HDAd) 的先天免疫反应成分进行了剖析，并证明了多种模式识别受体信号通路有助于宿主对 HDAd 的体内反应。基于细胞因子表达谱的分析，在注射后 1 小时，宿主小鼠肝脏中诱导产生 I 型干扰素 (IFN) mRNA。这种 I 型 IFN 信号在注射后 3 小时后独立于载体 DNA 序列的性质在肝脏中放大细胞因子的表达。这种对 HDAd 给药的 I 型 IFN 信号反应导致肝脏中 HDAd 原核和真核 DNA 的转录沉默。这种沉默发生得很早，并且如体内染色质免疫沉淀 (ChIP) 所示，通过抗组蛋白去乙酰化酶 (HDAC) 和早幼粒细胞白血病蛋白 (PML) 的表观遗传修饰介导。相比之下，与 HDAd 相比，自互补腺相关病毒载体 (scAAV) 在早期和晚期时间点在肝脏中诱导 I 型 IFN mRNA 的表达明显降低。这些结果表明，在肝脏定向基因转移后，AAV 和 HDAd 载体之间的 I 型 IFN 信号依赖性转基因沉默存在差异。
