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Updated: Jun 14, 2025

Stem-cell Based Engineered Immunity Against HIV Infection in the Humanized Mouse Model

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基于HSPC的抗HIV-1基因疗法使用安全杀死开关来防御和攻击HIV-1感染

Qi Guo^1,2,3, Keval Parikh^1,2, Jian Zhang^1,2

¹UCLA AIDS Institute, UCLA, Los Angeles, CA 90024, USA.

Molecular therapy. Methods & clinical development

|June 12, 2025

概括

这项研究介绍了一种新型基因疗法,使用造血干细胞/原始细胞 (HSPC) 来对抗HIV-1. 该疗法有效降低了小鼠的HIV-1病毒载量,并包括修改细胞的安全开关.

科学领域:

* 基因治疗基因治疗
* 病毒学病毒学
* 免疫学免疫学

背景情况:

* 造血干细胞/原始细胞 (HSPC) 基因疗法为HIV-1缓解提供了潜在的一次性,终身治疗.
*目前的策略需要多基因方法来有效地防御和攻击HIV-1.

研究的目的:

* 开发和评估一种基于HSPC的多方基因疗法,用于HIV-1抑制.
* 评估一种新型的lentiviral载体的有效性,同时表达抗HIV-1基因和安全开关.

主要方法:

* 设计了一种lentiviral载体,以共同表达CCR5shRNA,C46融合抑制剂和针对HIV-1的基于CD4的CAR.
* 包括一个截断的人类表皮生长因子受体 (huEGFRt) 作为安全杀死开关.
*转化了人类的CD34+HSPCs,并将它们移植到人性化骨髓/肝脏/肌肉组织 (huBLT) 的小鼠体内,随后进行HIV-1挑战和 cetuximab (CTX) 管理.

主要成果:

*转换的HSPCs在huBLT小鼠中有效地重建了多个血系的造血细胞.
* 在移植小鼠 (p < 0.001) 中观察到HIV-1病毒载荷 (1-log折叠) 的显著减少.
* Cetuximab的使用有效地耗尽了huEGFRt+载体修饰细胞 (>减少4倍,p <0.01).

结论:

*开发的多方基因疗法在抑制HIV-1方面非常有效.
* 通过 cetuximab 介导的负选择提供了一个可行的安全机制,如果发生不良反应,可以减少修饰后的细胞.

关键词:

在C46膜固的HIV-1融合抑制剂.CCR5 短毛RNA 是一种短毛RNA 基于CD4的抗HIV-1化学抗原受体.艾滋病病毒-1 艾滋病病毒-1 在体内通过 cetuximab 介导的负选择,人性化小鼠.基于血造干细胞/原始细胞 (HSPC) 的基因疗法截断的人类EGFR, huEGFRt

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