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Regulated zinc finger nucleases (ZFNs) by HIV-1 Tat to excise HIV-1 from host genome in infected and latently infected cells
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2018-05-03
Haiyan Ji, Panpan Lu, Baochi Liu, Xiying Qu, Yanan Wang, Zhengtao Jiang, Xinyi Yang, Yangcheng Zhong, He Yang, Hanyu Pan, Lin Zhao, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu

Highly active anti-retroviral therapy (HAART) cannot clear the infected cells harboring HIV-1 proviral DNA from the HIV-1 infected patients. We previously demonstrated that Zinc-finger nucleases (ZFNs) could specifically and efficiently excise HIV-1 proviral DNA from the latently infected human T cells by targeting the long terminal repeats (LTRs), a novel and alternative antiretroviral strategy for eradicating HIV-1 infection. To prevent the unwanted off-target effects from constantly expressed ZFNs, in this study, we engineered the expression of ZFNs under the control of HIV-1 LTR, by which ZFNs expression can be activated by the HIV-1 Tat protein. Our results show that functional expression of ZFNs induced by Tat excised the integrated proviral DNA of HIV-NL4-3-eGFP in approximate 30% population of HIV-1 infected cells. Meanwhile, the results from HIV-1 infected human primary T cells and latently infected T cells treated with the regulated ZFNs further validated proviral DNA could be excised. Taken together, positively regulated expression of ZFNs in the presence of HIV-1 Tat may provide a safer and novel implementation of the genome-editing technology for eradicating the HIV-1 proviral DNA from the infected host cells.



中文翻译:

HIV-1 Tat调节锌指核酸酶(ZFN),以从感染和潜伏感染细胞中的宿主基因组中切除HIV-1

高效抗逆转录病毒疗法(HAART)无法从感染HIV-1的患者中清除带有HIV-1前病毒DNA的感染细胞。我们先前证明,锌指核酸酶(ZFN)可以通过靶向长末端重复序列(LTR),从潜在感染的人类T细胞中特异性和有效地切除HIV-1前病毒DNA,这是一种新的替代性抗逆转录病毒策略,可消除HIV-1感染。为了防止持续表达的ZFN产生不必要的脱靶效应,在这项研究中,我们设计了HIV-1 LTR控制下ZFNs的表达,通过该表达,HIV-1 Tat蛋白可以激活ZFNs的表达。我们的结果表明,由Tat诱导的ZFNs的功能表达在大约30%的HIV-1感染细胞中切除了HIV-NL4-3-eGFP的整合前病毒DNA。同时,从HIV-1感染的人原代T细胞和用调节的ZFNs处理的潜伏感染的T细胞得到的结果可以进一步切除,以进一步验证原病毒DNA。综上所述,在存在HIV-1 Tat的情况下ZFNs的正向表达可能会为从受感染宿主细胞中消除HIV-1前病毒DNA的基因组编辑技术提供更安全,新颖的实施方法。

更新日期:2018-05-03
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