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首页> 外文期刊>Human gene therapy >Adeno-Associated Virus D-Sequence-Mediated Suppression of Expression of a Human Major Histocompatibility Class II Gene: Implications in the Development of Adeno-Associated Virus Vectors for Modulating Humoral Immune Response
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Adeno-Associated Virus D-Sequence-Mediated Suppression of Expression of a Human Major Histocompatibility Class II Gene: Implications in the Development of Adeno-Associated Virus Vectors for Modulating Humoral Immune Response

机译：腺相关病毒D-序列介导的人类主要组织相容性II类基因表达的抑制：对用于调节体液免疫应答的腺相关病毒载体的发育意义

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摘要

A 20-nt long sequence, termed the D-sequence, in the adeno-associated virus (AAV) inverted terminal repeat was observed to share a partial sequence homology with the X-box in the regulatory region of the human leukocyte antigen DRA (HLA-DRA) promoter of the human major histocompatibility complex class II (MHC-II) genes. The D-sequence was also shown to specifically interact with the regulatory factor binding to the X-box (RFX), binding of which to the X-box is a critical step in the MHC-II gene expression, suggesting that D-sequence might compete for RFX transcription factor binding, thereby suppressing expression from the MHC-II promoter. In DNA-mediated transfection experiments, using a reporter gene under the control of the HLA-DRA promoter, D-sequence oligonucleotides were found to inhibit expression of the reporter gene expression in HeLa and 293 cells by similar to 93% and 96%, respectively. No inhibition was observed when nonspecific synthetic oligonucleotides were used. D-sequence oligonucleotides had no effect on expression from the cytomegalovirus immediate-early gene promoter. Interferon-gamma-mediated activation of MHC-II gene expression was also inhibited by D-sequence oligonucleotides as well as after infection with either the wild-type AAV or transduction with recombinant AAV vectors. These studies suggest that the D-sequence-mediated downregulation of the MHC-II gene expression may be exploited toward the development of novel AAV vectors capable of dampening the host humoral response, which has important implication in the optimal use of these vectors in human gene therapy.
机译：在腺相关病毒（AAV）倒置末端重复中，将D-序列称为20-nt长序列，以与人白细胞抗原DRA的调节区（HLA）的X盒共享部分序列同源性（HLA -DRA）人类主要组织相容性复合体II类（MHC-II）基因的启动子。还显示D-序列与对X盒（RFX）结合的调节因子特异性相互作用，将其与X盒的结合是MHC-II基因表达中的关键步骤，表明D序列可能竞争RFX转录因子结合，从而抑制来自MHC-II启动子的表达。在DNA介导的转染实验中，在HLA-DRA启动子的控制下使用报告基因，发现D-序列寡核苷酸分别抑制HELA和293个细胞中的报告基因表达的表达，同样为93％和96％ 。当使用非特异性合成寡核苷酸时，不观察到抑制。 D-序列寡核苷酸对巨细胞病毒立即早期基因启动子的表达没有影响。通过D序列寡核苷酸以及用重组AAV载体的野生型AAV或转导感染，也抑制了MHC-II基因表达的干扰素介导的MHC-II基因表达的活化。这些研究表明，MHC-II基因表达的D-序列介导的下调可以利用新型AAV载体的开发能够抑制宿主体液反应，这在人类基因中最佳使用这些载体中具有重要意义治疗。

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