HIV-1 inhibition in cells with CXCR4 mutant genome created by CRISPR-Cas9 and piggyBac recombinant technologies

The C-X-C chemokine receptor type 4 (CXCR4) is one of the major co-receptors for human immunodeficiency virus type 1 (HIV-1) entry and is considered an important therapeutic target. However, its function in maintaining the development of hematopoietic stem cells (HSC) makes it difficult to be used f...

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Bibliographic Details
Published in:Scientific reports 2018-06, Vol.8 (1), p.8573-11, Article 8573
Main Authors: Liu, Shuai, Wang, Qiankun, Yu, Xiao, Li, Yilin, Guo, Yandan, Liu, Zhepeng, Sun, Fuyun, Hou, Wei, Li, Chunmei, Wu, Li, Guo, Deyin, Chen, Shuliang
Format: Article
Language:English
Subjects:
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631/208/726/649/2157
631/61/201/2110
CRISPR
CXCR4 protein
Gene therapy
Genomes
Hematopoietic stem cells
HIV
Homologous recombination
Human immunodeficiency virus
Humanities and Social Sciences
Infections
multidisciplinary
Mutants
Science
Science (multidisciplinary)
Stem cells
Therapeutic applications
Transplantation
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Summary:The C-X-C chemokine receptor type 4 (CXCR4) is one of the major co-receptors for human immunodeficiency virus type 1 (HIV-1) entry and is considered an important therapeutic target. However, its function in maintaining the development of hematopoietic stem cells (HSC) makes it difficult to be used for HIV-1 gene therapy with HSC transplantation. A previous report showed that the natural CXCR4 P191A mutant inhibits HIV-1 infection without any defect in HSC differentiation, which could provide a basis for the development of new approaches for HIV-1 gene therapy. In the present study, we used CRISPR-Cas9 combined with the piggyBac transposon technologies to efficiently induce the expression of the CXCR4 P191A mutant in an HIV-1 reporter cell line, leading to no detectable exogenous sequences. In addition, no off-target effects were detected in the genome-edited cells. The decline of HIV-1 replication in biallelic CXCR4 gene-edited cells suggests that individuals equipped with homologous recombination of the CXCR4 P191A mutant could prevent or reduce HIV-1 infection. This study provides an effective approach to create a CXCR4 mutation with HIV-1 infection inhibition function and without leaving any genetic footprint inside cells, thereby shedding light on an application in HIV-1 gene therapy and avoiding side effects caused by deficiency or destruction of CXCR4 function.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-26894-4