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首页> 美国卫生研究院文献>Journal of Virology >Generation of an HIV-1-Resistant Immune System with CD34+ Hematopoietic Stem Cells Transduced with a Triple-Combination Anti-HIV Lentiviral Vector
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Generation of an HIV-1-Resistant Immune System with CD34+ Hematopoietic Stem Cells Transduced with a Triple-Combination Anti-HIV Lentiviral Vector

机译：具有三结合抗HIV慢病毒载体转导的CD34 +造血干细胞的HIV-1抗性免疫系统的生成。

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HIV gene therapy has the potential to offer an alternative to the use of current small-molecule antiretroviral drugs as a treatment strategy for HIV-infected individuals. Therapies designed to administer HIV-resistant stem cells to an infected patient may also provide a functional cure, as observed in a bone marrow transplant performed with hematopoietic stem cells (HSCs) homozygous for the CCR5-Δ32-bp allele. In our current studies, preclinical evaluation of a combination anti-HIV lentiviral vector was performed, in vivo, in humanized NOD-RAG1−/− IL2rγ−/− knockout mice. This combination vector, which displays strong preintegration inhibition of HIV-1 infection in vitro, contains a human/rhesus macaque TRIM5α isoform, a CCR5 short hairpin RNA (shRNA), and a TAR decoy. Multilineage hematopoiesis from anti-HIV lentiviral vector-transduced human CD34+ HSCs was observed in the peripheral blood and in various lymphoid organs, including the thymus, spleen, and bone marrow, of engrafted mice. Anti-HIV vector-transduced CD34+ cells displayed normal development of immune cells, including T cells, B cells, and macrophages. The anti-HIV vector-transduced cells also displayed knockdown of cell surface CCR5 due to the expression of the CCR5 shRNA. After in vivo challenge with either an R5-tropic BaL-1 or X4-tropic NL4-3 strain of HIV-1, maintenance of human CD4+ cell levels and a selective survival advantage of anti-HIV gene-modified cells were observed in engrafted mice. The data provided from our study confirm the safety and efficacy of this combination anti-HIV lentiviral vector in a hematopoietic stem cell gene therapy setting for HIV and validates its potential application in future clinical trials.
机译：HIV基因疗法有可能为使用当前的小分子抗逆转录病毒药物提供替代方案，作为针对HIV感染者的治疗策略。如对CCR5-Δ32-bp等位基因纯合的造血干细胞（HSC）进行的骨髓移植所观察到的，设计用于向感染患者施用HIV抵抗性干细胞的疗法也可提供功能性治愈。在我们当前的研究中，在人源化的NOD-RAG1 -/-IL2rγ-/-敲除小鼠体内进行了抗HIV慢病毒组合载体的临床前评价。该组合载体在体外显示出对HIV-1感染的强大的整合前抑制作用，该组合载体包含人/猕猴TRIM5α亚型，CCR5短发夹RNA（shRNA）和TAR诱饵。在移植小鼠的外周血和包括胸腺，脾脏和骨髓在内的各种淋巴器官中，观察到了由抗HIV慢病毒载体转导的人CD34 + HSC的多谱系造血作用。抗HIV载体转导的CD34 + 细胞表现出免疫细胞的正常发育，包括T细胞，B细胞和巨噬细胞。由于CCR5 shRNA的表达，抗HIV载体转导的细胞还显示出细胞表面CCR5的敲低。用HIV的R5嗜性BaL-1或X4嗜性NL4-3毒株进行体内攻击后，维持人CD4 + 细胞水平和抗HIV基因的选择性存活优势在植入的小鼠中观察到修饰的细胞。我们的研究提供的数据证实了该组合抗HIV慢病毒载体在HIV造血干细胞基因治疗中的安全性和有效性，并验证了其在未来临床试验中的潜在应用。

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