Molecular Microbiology & Immunology, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
Curr Opin HIV AIDS. 2011 Jan;6(1):74-9. doi: 10.1097/COH.0b013e32834122d7.
Individuals homozygous for a deletion in the chemokine receptor 5 (CCR5) gene (CCR5Δ32) are almost completely resistant to HIV-1 infection. A recent report that transplantation of hematopoietic stem or progenitor cells (HSCs) from a CCR5Δ32 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.
CCR5 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.
CCR5 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.
趋化因子受体 5（CCR5）基因缺失的个体（CCR5Δ32）对 HIV-1 感染几乎完全具有抗性。最近有报道称，从 CCR5Δ32 纯合供体移植造血干细胞或祖细胞（HSCs）有效地治愈了一名 HIV 患者，这增加了人们对开发策略的兴趣，这些策略可以使用患者自身的细胞来重现这种表型。这篇综述将重点介绍最近在自体 T 细胞和 HSCs 中破坏 CCR5 表达的研究进展。
RNA 干扰等基于 RNA 的基因抑制技术可抑制 HIV-1 靶细胞中 CCR5 的表达，或通过锌指核酸酶（ZFN）介导的基因破坏将其完全消除。ZFN 特异性地结合到 DNA 序列上，并产生双链 DNA 断裂，随后细胞易错的非同源末端连接途径修复该断裂可导致基因开放阅读框的永久性破坏。人源化小鼠模型的最新进展促进了临床前研究，这些研究表明，当用于修饰人 T 细胞或 HSCs 时，靶向 CCR5 的 ZFN 可在体内抑制 HIV-1。相同的 CCR5 ZFN 目前正在一项使用离体扩增自体 T 细胞的 I 期临床试验中进行评估。
ZFN 在 T 细胞或 HSCs 中对 CCR5 基因的敲除可有效抑制动物模型中 CCR5 嗜性 HIV-1 株的复制。ZFN 目前正在使用离体扩增 T 细胞和 HSCs 的 I 期临床试验中进行评估，靶向治疗方法正在开发中。
