Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA.
Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA.
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DOI：
10.1016/j.omtn.2018.07.017
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发表时间：
2018-09-07
期刊：
影响因子：
--
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Higaki K;Hirao M;Kawana-Tachikawa A;Iriguchi S;Kumagai A;Ueda N;Bo W;Kamibayashi S;Watanabe A;Nakauchi H;Suzuki K;Kaneko S
高效抗逆转录病毒疗法(HAART)显著延长了HIV-1患者的预后。然而，对HAART的终生依赖是一个持续的挑战，非常需要有效的治疗方法。最近，针对HIV-1启动子的短发夹状RNA(ShRNA)的引入被发现通过转录基因沉默(TGS)抑制HIV-1的复制。这项技术有望应用于艾滋病毒患者的血淋巴细胞移植，以抑制移植的血淋巴细胞中的艾滋病毒转录。将TGS技术与新的细胞移植策略与诱导多能干细胞(IPSC)来源的造血细胞相结合，可能有助于HIV领域的新的基因治疗。在这项研究中，我们评估了IPSC来源的巨噬细胞的功能和TGS技术在巨噬细胞中的可行性。利用慢病毒载体将针对HIV-1启动子区域(ShPromA)的shRNAs导入人IPSCs。通过改变HIV-1启动子区域的组蛋白结构，诱导异染色质的形成，成功地将shPromA基因导入的IPSCs分化为有功能的巨噬细胞，并对HIV-1复制表现出很强的保护作用。这些结果表明，iPS来源的巨噬细胞是研究HIV感染和保护的有用工具，针对HIV启动子的TGS技术是新的基因治疗的潜在候选者。
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.
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影响因子：
46.9
作者：
Jackson, AL;Bartz, SR;Linsley, PS
通讯作者：
Linsley, PS
DOI：
10.1038/mtna.2015.31
发表时间：
2015-10-27
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
Ahlenstiel C;Mendez C;Lim ST;Marks K;Turville S;Cooper DA;Kelleher AD;Suzuki K
通讯作者：
Suzuki K
影响因子：
64.8
作者：
Goldstone, David C.;Ennis-Adeniran, Valerie;Webb, Michelle
通讯作者：
Webb, Michelle
影响因子：
5.4
作者：
Coburn, GA;Cullen, BR
通讯作者：
Cullen, BR
影响因子：
158.5
作者：
Huetter, Gero;Nowak, Daniel;Thiel, Eckhard
通讯作者：
Thiel, Eckhard