Chemokine receptor 5 knockout strategies
Chemokine receptor 5 knockout strategies
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DOI：
10.1097/coh.0b013e32834122d7
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发表时间：
2011-01-01
影响因子：
4.1
通讯作者：
June, Carl
中科院分区：
文献类型：
--
作者：
Cannon, Paula;June, Carl
审查目的趋化因子受体 5 (CCR5) 基因 (CCR5 Delta 32) 缺失的纯合个体几乎完全抵抗 HIV-1 感染。最近的一份报告称，移植来自 CCR5 Delta 32 纯合子供体的造血干细胞或祖细胞 (HSC) 可以有效治愈 HIV 患者，这增加了人们对开发可用于利用患者自身细胞重建这种表型的策略的兴趣。本综述将重点关注破坏自体 T 细胞和 HSC 中 CCR5 表达的最新进展。最新发现 HIV-1 靶细胞中的 CCR5 表达可以通过基于 RNA 的基因抑制技术（例如 RNA 干扰）抑制，或通过锌指核酸酶 (ZFN) 介导的基因破坏完全消除。 ZFN 特异性结合 DNA 序列并产生双链 DNA 断裂，随后细胞容易出错的非同源末端连接途径对其进行修复，可导致基因开放阅读框的永久破坏。人源化小鼠模型的最新发展促进了临床前研究，这些研究证明了当用于修饰人类 T 细胞或 HSC 时，靶向 CCR5 的 ZFN 能够在体内抑制 HIV-1。目前正在离体扩增自体 T 细胞的 I 期临床试验中评估相同的 CCR5 ZFN。总结 ZFN 在 T 细胞或 HSC 中敲除 CCR5 基因可有效抑制动物模型中 HIV-1 的 CCR5 嗜性株的复制。 ZFN 目前正在使用离体扩增 T 细胞的 I 期临床试验中进行评估，HSC 靶向疗法正在开发中。
Purpose of reviewIndividuals homozygous for a deletion in the chemokine receptor 5 (CCR5) gene (CCR5 Delta 32) are almost completely resistant to HIV-1 infection. A recent report that transplantation of hematopoietic stem or progenitor cells (HSCs) from a CCR5 Delta 32 homozygous donor effectively cured an HIV patient has increased interest in the development of strategies that could be used to recreate this phenotype using a patient's own cells. This review will focus on recent developments to disrupt CCR5 expression in both autologous T cells and HSCs.Recent findingsCCR5 expression in HIV-1 target cells can be suppressed by RNA-based gene suppression technologies such as RNA interference, or completely eliminated by zinc finger nuclease (ZFN)-mediated gene disruption. ZFNs bind specifically to a DNA sequence and generate a double-stranded DNA break, whose subsequent repair by the cell's error-prone nonhomologous end-joining pathway can lead to permanent disruption of the gene's open reading frame. Recent developments in humanized mouse models have facilitated preclinical studies that have demonstrated the ability of CCR5-targeted ZFNs to suppress HIV-1 in vivo, when used to modify human T cells or HSCs. The same CCR5 ZFNs are now being evaluated in a phase I clinical trial of ex vivo expanded autologous T cells.SummaryCCR5 gene knockout in T cells or HSCs by ZFNs effectively suppresses the replication of CCR5-tropic strains of HIV-1 in animal models. ZFNs are currently being evaluated in a phase I clinical trials using ex vivo expanded T cells and HSCs targeted therapies are under development.