Stem Cell Rep :一种新方法揭示HIV如何影响大脑认知功能!

2020-03-30 生物探索 生物探索

目前抗逆转录病毒疗法(antiretroviral therapy, ART)普遍应用于人体免疫缺陷病毒感染,即便如此,50%以上的HIV患者仍表现出健忘、困惑、行为改变和运动缺陷等症状

目前抗逆转录病毒疗法(antiretroviral therapy, ART)普遍应用于人体免疫缺陷病毒感染,即便如此,50%以上的HIV患者仍表现出健忘、困惑、行为改变和运动缺陷等症状,即HIV相关的神经认知障碍(HIV-associated neurocognitive disorders,HAND),但由于HAND的作用机制不明确,也缺乏代表性模型,导致无法针对性治疗。

近日,佩恩牙科医学院和佩勒曼医学院以及费城儿童医院的研究者们建立了一种基于人诱导多能干细胞(human-induced pluripotent stem cell, hiPSC)的模型,发现HIV感染会增强小胶质细胞、星形胶质细胞和神经元的EIF2信号。该研究发表在《Stem Cell Reports》期刊上。


DOI: 10.1016/j.stemcr.2020.02.010

通常认为,神经元不直接接触HIV,而是在感染中受损;星形胶质细胞会向突触发送促炎症因子而造成损伤;负责维持健康环境的小胶质细胞在HIV感染期间会扩张并导致炎症。研究者独立地将hiPSCs分化为前脑样兴奋性神经元、星形胶质细胞和小胶质细胞三种类型,然后混合在一起,利用这种培养基来探索HIV感染和ART如何影响细胞。


三种细胞的分化流程,之后将其结合为Tri-culture(±HIV感染和ART)

对带有HIV感染的小胶质细胞的三种培养物进行单细胞RNA序列分析,检测到三种细胞类型细胞中存在EIF2信号,小胶质细胞中有炎症信号。之后,用EFZ(efavirenz)——抗逆转录病毒化合物治疗则极大地解决了这些特征,同时也增加了HIV感染的小胶质细胞中的RhoGDI和CD40信号,这与小胶质细胞所产的转化生长因子α的持续增加有关。


HIV感染的hiPSC Tri-culture模型中,ART治疗仍伴随神经炎症和EIF2信号存在

综上,研究者描述了源于hiPSC的小胶质细胞、星形胶质细胞和神经元的三种培养方法,并发现HIV感染会导致所有三种细胞类型的EIF2信号增强,而EFZ的单独治疗可通过RNA的表达来产生炎症信号,此外,感染的小胶质细胞可增加炎症反应,减少突触的吞噬功能。未来,希望更多科学家们可以探究HIV对大脑影响的其他方面,例如:HIV如何通过血脑屏障等。

原始出处:

James P. Garifallou, Michael V. Gonzalez, Sean K. Ryan, et.al. Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection. Stem Cell Rep March 26, 2020

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    2020-12-27 docwu2019
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