CRISPR/Cas9-mediated deletion of miR-146a enhances antiviral response in HIV-1 infected cells.
CRISPR/Cas9-mediated deletion of miR-146a enhances antiviral response in HIV-1 infected cells.
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CRISPR/Cas9 介导的 miR-146a 缺失增强了 HIV-1 感染细胞的抗病毒反应。
DOI：
10.1038/s41435-018-0036-x
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Feng Yong
中科院分区：
文献类型：
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作者：
Teng Yan;Luo Mingqi;Yu Ting;Chen Lang;Huang Qiuling;Chen Shuliang;Xie Linlin;Zeng Yan;Luo Fan;Xiong Hairong;Liu Yuanyuan;Hou Wei;Feng Yong
人类免疫缺陷病毒1型（human immunodeficiency virus type 1，HIV-1）在人体内引起持续感染，并诱导感染细胞中miR-146 a表达。miR-146 a通过抑制TRAF 6和IRAK 1基因的表达，抑制天然免疫应答，从而负性调控NF-κ B相关的细胞因子和干扰素刺激基因。在此，我们报道了慢病毒CRISPR/Cas9系统在前体miR-146 a基因组序列中高效引入突变，导致miR-146 a表达和功能丧失。miR-146 a消融导致LPS刺激的A549细胞中细胞因子产生增加。此外，miR-146 a敲除在HIV-1感染的MT 2细胞中显著增加细胞因子和HIV-1限制性因子的表达，并逆转T细胞耗竭标记物的表达，从而影响HIV-1复制。我们的研究表明，慢病毒CRISPR/Cas9介导的基因编辑是消除miR-146 a表达的有效方法，从而通过增强细胞因子和HIV-1限制因子的表达来抑制HIV-1复制以及前病毒再激活。
The human immunodeficiency virus type 1 (HIV-1) causes persistent infection in human and induces miR-146a expression in infected cells. miR-146a represses the innate immune response by inhibiting the expression ofTRAF6andIRAK1genes, thus negatively controls the NF-κB-related cytokines and interferon stimulated genes. Here we reported that lentiviral CRISPR/Cas9 system was highly efficient in introducing mutations in the precursor miR-146a genomic sequences, resulting in a loss of miR-146a expression and function. miR-146a ablation led to increasing cytokines production in LPS-stimulated A549 cells. Moreover, miR-146a knockout in HIV-1 infected MT2 cells markedly increased the expression of cytokines and HIV-1 restriction factors and reversed T cell exhaustion markers expression, thus influencing HIV-1 replication. Our study indicates that lentiviral CRISPR/Cas9-mediated gene editing is an effective approach to abrogate miR-146a expression, which consequently inhibits HIV-1 replication as well as proviral reactivation by enhancing the expression of cytokines and HIV-1 restriction factors.