Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells
Highly active anti-retroviral therapy (HAART) cannot clear infected cells harboring HIV-1 proviral DNA from HIV-1-infected patients. We previously demonstrated that zinc-finger nucleases (ZFNs) can specifically and efficiently excise HIV-1 proviral DNA from latently infected human T cells by targeti...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225311830088X |
| _version_ | 1818527552173506560 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Haiyan Ji |
| collection | DOAJ |
| description | Highly active anti-retroviral therapy (HAART) cannot clear infected cells harboring HIV-1 proviral DNA from HIV-1-infected patients. We previously demonstrated that zinc-finger nucleases (ZFNs) can specifically and efficiently excise HIV-1 proviral DNA from latently infected human T cells by targeting long terminal repeats (LTRs), a novel and alternative antiretroviral strategy for eradicating HIV-1 infection. To prevent 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 ZFN expression can be activated by the HIV-1 (Trans-Activator of Transcription) Tat protein. Our results show that functional expression of ZFNs induced by Tat excise the integrated proviral DNA of HIV-NL4-3-eGFP in approximately 30% of the population of HIV-1-infected cells. The results from HIV-1-infected human primary T cells and latently infected T cells treated with the inducible ZFNs further validated that proviral DNA can be excised. Taken together, positively regulated expression of ZFNs in the presence of HIV-1 Tat may provide a safer and novel implementation of genome-editing technology for eradicating HIV-1 proviral DNA from infected host cells. Keywords: zinc-finger nuclease, genome editing, genomic excision, inducible, Tat, HIV-1, gene therapy |
| first_indexed | 2024-12-11T06:37:35Z |
| format | Article |
| id | doaj.art-3492fa03c2d042ff8838feef759b40c0 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-11T06:37:35Z |
| publishDate | 2018-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-3492fa03c2d042ff8838feef759b40c02022-12-22T01:17:20ZengElsevierMolecular Therapy: Nucleic Acids2162-25312018-09-01126774Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected CellsHaiyan Ji0Panpan Lu1Baochi Liu2Xiying Qu3Yanan Wang4Zhengtao Jiang5Xinyi Yang6Yangcheng Zhong7He Yang8Hanyu Pan9Lin Zhao10Jianqing Xu11Hongzhou Lu12Huanzhang Zhu13State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaShanghai Public Health Clinical Center, Fudan University, Shanghai 200433, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, ChinaShanghai Public Health Clinical Center, Fudan University, Shanghai 200433, ChinaShanghai Public Health Clinical Center, Fudan University, Shanghai 200433, ChinaState Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Gene & Cell Therapy Research Center, School of Life Sciences, Fudan University, Shanghai 200438, China; Corresponding author: Huanzhang Zhu, State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of the Ministry of Education/Health, Center of Gene Therapy, School of Life Sciences, Fudan University, Shanghai 200438, China.Highly active anti-retroviral therapy (HAART) cannot clear infected cells harboring HIV-1 proviral DNA from HIV-1-infected patients. We previously demonstrated that zinc-finger nucleases (ZFNs) can specifically and efficiently excise HIV-1 proviral DNA from latently infected human T cells by targeting long terminal repeats (LTRs), a novel and alternative antiretroviral strategy for eradicating HIV-1 infection. To prevent 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 ZFN expression can be activated by the HIV-1 (Trans-Activator of Transcription) Tat protein. Our results show that functional expression of ZFNs induced by Tat excise the integrated proviral DNA of HIV-NL4-3-eGFP in approximately 30% of the population of HIV-1-infected cells. The results from HIV-1-infected human primary T cells and latently infected T cells treated with the inducible ZFNs further validated that proviral DNA can be excised. Taken together, positively regulated expression of ZFNs in the presence of HIV-1 Tat may provide a safer and novel implementation of genome-editing technology for eradicating HIV-1 proviral DNA from infected host cells. Keywords: zinc-finger nuclease, genome editing, genomic excision, inducible, Tat, HIV-1, gene therapyhttp://www.sciencedirect.com/science/article/pii/S216225311830088X |
| spellingShingle | 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 Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells Molecular Therapy: Nucleic Acids |
| title | Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells |
| title_full | Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells |
| title_fullStr | Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells |
| title_full_unstemmed | Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells |
| title_short | Zinc-Finger Nucleases Induced by HIV-1 Tat Excise HIV-1 from the Host Genome in Infected and Latently Infected Cells |
| title_sort | zinc finger nucleases induced by hiv 1 tat excise hiv 1 from the host genome in infected and latently infected cells |
| url | http://www.sciencedirect.com/science/article/pii/S216225311830088X |
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