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Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection.

Genome modification of CXCR4 by Staphylococcus aureus Cas9 renders cells resistance to HIV-1 infection.
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Wang Q, Chen S, Xiao Q, Liu Z, Liu S, Hou P, Zhou L, Hou W, Ho W, Li C, Wu L, Guo D,


Wang Q, Chen S, Xiao Q, Liu Z, Liu S, Hou P, Zhou L, Hou W, Ho W, Li C, Wu L, Guo D, (click to view)

Wang Q, Chen S, Xiao Q, Liu Z, Liu S, Hou P, Zhou L, Hou W, Ho W, Li C, Wu L, Guo D,

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Retrovirology 2017 11 1514(1) 51 doi 10.1186/s12977-017-0375-0

Abstract
BACKGROUND
The CRISPR/Cas9 system has been widely used for genome editing in mammalian cells. CXCR4 is a co-receptor for human immunodeficiency virus type 1 (HIV-1) entry, and loss of CXCR4 function can protect cells from CXCR4 (X4)-tropic HIV-1 infection, making CXCR4 an important target for HIV-1 gene therapy. However, the large size of the CRISPR/SpCas9 system presents an obstacle to its efficient delivery into primary CD4(+) T cells. Recently, a small Staphylococcus aureus Cas9 (SaCas9) has been developed as a genome editing tool can address this question. Therefore, it provides a promising strategy for HIV-1 gene therapy if it is used to target CXCR4.

RESULTS
Here, we employed a short version of Cas9 from Staphylococcus aureus (SaCas9) for targeting CXCR4. We demonstrated that transduction of lenti-virus expressing SaCas9 and selected single-guided RNAs of CXCR4 in human CD4(+) T cell lines efficiently induced the editing of the CXCR4 gene, making these cell lines resistant to X4-tropic HIV-1 infection. Moreover, we efficiently transduced primary human CD4(+) T cells using adeno-associated virus-delivered CRISPR/SaCas9 and disrupted CXCR4 expression. We also showed that CXCR4-edited primary CD4(+) T cells proliferated normally and were resistant to HIV-1 infection.

CONCLUSIONS
Our study provides a basis for possible application of CXCR4-targeted genome editing by CRISPR/SaCas9 in HIV-1 gene therapy.

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