TALEN-Mediated Knockout of CCR5 Confers Protection Against Infection of Human Immunodeficiency Virus | |
Shi, Bingjie ; Li, Juan ; Shi, Xuanling ; Jia, Wenxu ; Wen, Yi ; Hu, Xiongbing ; Zhuang, Fengfeng ; Xi, Jianzhong ; Zhang, Linqi | |
刊名 | JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES |
2017 | |
关键词 | HIV-1 CCR5 genome editing TALEN and ZFN ZINC-FINGER NUCLEASES DEFICIENCY-SYNDROME AIDS OFF-TARGET CLEAVAGE CD4(+) T-CELLS HIV-1 INFECTION DISEASE PROGRESSION CORECEPTOR USAGE IN-VIVO EFFECTOR NUCLEASES HEMATOPOIETIC STEM |
英文摘要 | Transcription activator-like effector nuclease (TALEN) represents a valuable tool for genomic engineering due to its single-nucleotide precision, high nuclease activity, and low cytotoxicity. We report here systematic design and characterization of 28 novel TALENs targeting multiple regions of CCR5 gene (CCR5-TALEN) which encodes the co-receptor critical for entry of human immunodeficiency virus type I (HIV-1). By systemic characterization of these CCR5-TALENs, we have identified one (CCR5-TALEN-515) with higher nuclease activity, specificity, and lower cytotoxicity compared with zinc-finger nuclease (CCR5-ZFN) currently undergoing clinical trials. Sequence analysis of target cell line GHOST-CCR5-CXCR4 and human primary CD4(+) T cells showed that the double-strand breaks at the TALEN targeted sites resulted in truncated or nonfunctional CCR5 proteins thereby conferring protection against HIV-1 infection in vitro. None of the CCR5-TALENs had detectable levels of off-target nuclease activity against the homologous region in CCR2 although substantial level was identified for CCR5-ZFN in the primary CD4(+) T cells. Our results suggest that the CCR5-TALENs identified here are highly functional nucleases that produce protective genetic alterations to human CCR5. Application of these TALENs directly to the primary CD4(+) T cells and CD34(+) hematopoietic stem cells (HSCs) of infected individuals could help to create an immune system resistant to HIV-1 infection, recapitulating the success of "Berlin patient" and serving as an essential first step towards a "functional" cure of AIDS.; Beijing Municipal Science and Technology Commission [Z121100005212002]; National Natural Science Foundation Award [81530065]; Ministry of Science and Technology of China [2014CB5425000-03]; Janssen Investigator Award; SCI(E); ARTICLE; 2; 229-241; 74 |
语种 | 英语 |
内容类型 | 期刊论文 |
源URL | [http://ir.pku.edu.cn/handle/20.500.11897/475309] |
专题 | 工学院 |
推荐引用方式 GB/T 7714 | Shi, Bingjie,Li, Juan,Shi, Xuanling,et al. TALEN-Mediated Knockout of CCR5 Confers Protection Against Infection of Human Immunodeficiency Virus[J]. JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES,2017. |
APA | Shi, Bingjie.,Li, Juan.,Shi, Xuanling.,Jia, Wenxu.,Wen, Yi.,...&Zhang, Linqi.(2017).TALEN-Mediated Knockout of CCR5 Confers Protection Against Infection of Human Immunodeficiency Virus.JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES. |
MLA | Shi, Bingjie,et al."TALEN-Mediated Knockout of CCR5 Confers Protection Against Infection of Human Immunodeficiency Virus".JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES (2017). |
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