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Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA.
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2018-08-04 , DOI: 10.1016/j.omtn.2018.07.017
Kei Higaki 1 , Masako Hirao 1 , Ai Kawana-Tachikawa 2 , Shoichi Iriguchi 1 , Ayako Kumagai 1 , Norihiro Ueda 1 , Wang Bo 1 , Sanae Kamibayashi 1 , Akira Watanabe 3 , Hiromitsu Nakauchi 4 , Kazuo Suzuki 5 , Shin Kaneko 1
Affiliation  

Highly active antiretroviral therapy (HAART) has markedly prolonged the prognosis of HIV-1 patients. However, lifelong dependency on HAART is a continuing challenge, and an effective therapeutic is much desired. Recently, introduction of short hairpin RNA (shRNA) targeting the HIV-1 promoter was found to suppress HIV-1 replication via transcriptional gene silencing (TGS). The technology is expected to be applied with hemato-lymphopoietic cell transplantation of HIV patients to suppress HIV transcription in transplanted hemato-lymphopoietic cells. Combination of the TGS technology with new cell transplantation strategy with induced pluripotent stem cell (iPSC)-derived hemato-lymphopoietic cells might contribute to new gene therapy in the HIV field. In this study, we evaluated iPSC-derived macrophage functions and feasibility of TGS technology in macrophages. Human iPSCs were transduced with shRNAs targeting the HIV-1 promoter region (shPromA) by using a lentiviral vector. The shPromA-transfected iPSCs were successfully differentiated into functional macrophages, and they exhibited strong protection against HIV-1 replication with alteration in the histone structure of the HIV-1 promoter region to induce heterochromatin formation. These results indicated that iPS-derived macrophage is a useful tool to investigate HIV infection and protection, and that the TGS technology targeting the HIV promoter is a potential candidate of new gene therapy.



中文翻译:

通过使用转录基因沉默和启动子靶向RNA,从IPSC产生抗HIV的巨噬细胞。

高效抗逆转录病毒疗法(HAART)显着延长了HIV-1患者的预后。然而,终身依赖HAART是一个持续的挑战,非常需要有效的治疗方法。最近,发现针对HIV-1启动子的短发夹RNA(shRNA)的引入可通过转录基因沉默(TGS)抑制HIV-1复制。该技术有望与HIV患者的血液淋巴细胞细胞移植一起使用,以抑制移植的血液淋巴细胞细胞中的HIV转录。将TGS技术与新的细胞移植策略与诱导的多能干细胞(iPSC)衍生的造血淋巴细胞结合起来,可能有助于HIV领域的新基因治疗。在这项研究中,我们评估了iPSC衍生的巨噬细胞功能和TGS技术在巨噬细胞中的可行性。通过使用慢病毒载体,用靶向HIV-1启动子区域(shPromA)的shRNA转导人iPSC。shPromA转染的iPSCs已成功分化为功能性巨噬细胞,并且通过改变HIV-1启动子区域的组蛋白结构来诱导异染色质形成,它们对HIV-1复制表现出强大的保护作用。这些结果表明,源自iPS的巨噬细胞是研究HIV感染和保护的有用工具,针对HIV启动子的TGS技术是新基因疗法的潜在候选者。shPromA转染的iPSCs已成功分化为功能性巨噬细胞,并且通过改变HIV-1启动子区域的组蛋白结构来诱导异染色质形成,它们对HIV-1复制表现出强大的保护作用。这些结果表明,源自iPS的巨噬细胞是研究HIV感染和保护的有用工具,针对HIV启动子的TGS技术是新基因疗法的潜在候选者。shPromA转染的iPSCs已成功分化为功能性巨噬细胞,并且通过改变HIV-1启动子区域的组蛋白结构来诱导异染色质形成,它们对HIV-1复制表现出强大的保护作用。这些结果表明,源自iPS的巨噬细胞是研究HIV感染和保护的有用工具,针对HIV启动子的TGS技术是新基因疗法的潜在候选者。

更新日期:2018-08-04
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