HIV Receives a "One Two Knockout Punch".
HIV Receives a "One Two Knockout Punch".
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HIV 受到“一二击倒”。
DOI：
10.1016/j.ymthe.2017.02.001
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Bollard,CatherineM
中科院分区：
文献类型：
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作者：
Cruz,ConradRussell;Bollard,CatherineM
T 细胞疗法已显示出对抗病毒感染和恶性肿瘤的希望。此外，基因编辑技术的进步有望通过基因修饰、删除或添加来增强 T 细胞的效力。 1 在本期《分子治疗》中，Hale 等人 2 在单一构建体中，将 CCR5 敲低与靶向 HIV 包膜的嵌合抗原受体结合起来，这种组合策略可以提供独立于主要组织相容性复合体 (MHC) 表达的抗 HIV 活性，并保护基因修饰的 T 细胞免受 HIV 感染。利用内源同源定向重组 (HDR) 途径引入基因修饰是增强 T 细胞治疗的一种有前景的策略。利用 HDR 进行基因修饰涉及使用外源 DNA 模板来指定 DNA 双链断裂修复的确切结果。换句话说，当引入靶向DNA双链断裂时，HDR机器可以使用外源提供的单链或双链DNA模板（与断裂位点具有序列同源性）来合成用于修复损伤的DNA，从而允许在断裂位点精确插入基因产物。 3 例如，研究表明，这种机制可用于特异性选择转基因可以表达的区域（限制插入诱变事件），或者更有趣的是，同时破坏表达不需要的基因的区域并用外源（或有利）基因构建体替换它。 4
T cell therapies have shown promise against viral infections and malignancies. Moreover, advances in gene-editing technology hold the promise that T cell potency can be enhanced by gene modification, deletion, or addition. 1 In this issue of Molecular Therapy, Hale et al., 2 in a single construct, combine CCR5 knockdown with a chimeric antigen receptor targeting the HIV envelope, a combination strategy that can potentially provide both anti-HIV activity independent of major histocompatibility complex (MHC) expression and protection of gene-modified T cells from HIV infection.Exploitation of endogenous homologydirected recombination (HDR) pathways to introduce genetic modifications is a promising strategy to enhance T cell therapies. Harnessing HDR for gene modification involves the use of an exogenous DNA template to specify the exact outcome of DNA double-strand break repair. In other words, when a targeted DNA double-strand break is introduced, the HDR machinery can use exogenously provided single-or double-stranded DNA templates (which have sequence homology to the break site) to synthesize DNA that is used to repair the lesion, allowing for the precise insertion of gene products at the break site. 3 For example, it was shown that such a mechanism may be utilized to specifically select a region where a transgene can be expressed (limiting insertional mutagenesis events) or, more intriguingly, to simultaneously disrupt a region expressing an unwanted gene and replace it with a foreign (or favorable) genetic construct. 4