HIV-1 infection of genetically engineered iPSC-derived central nervous system-engrafted microglia in a humanized mouse model.
HIV-1 infection of genetically engineered iPSC-derived central nervous system-engrafted microglia in a humanized mouse model.
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DOI：
10.1128/jvi.01595-23
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发表时间：
2023-12-21
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
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作者：
中枢神经系统(CNS)是人类免疫缺陷病毒1型(HIV-1)的主要宿主。小胶质细胞是HIV-1感染中枢神经系统的主要靶细胞。目前的模型还不允许用体内遗传学方法测试急性和慢性中枢神经系统小胶质细胞感染的确切分子途径。在这里，我们描述了一种新颖的人源化小鼠模型，利用人诱导的多能干细胞(IPSC)来源的小胶质细胞异种移植到小鼠宿主体内。这些小鼠还被植入了人外周血单个核细胞，作为建立外周感染的媒介，然后传播到CNS小胶质细胞异种移植，用人类靶细胞模拟急性CNS HIV-1感染的跨血脑屏障途径。该方法与IPSC基因工程相兼容，包括插入有针对性的转基因报告盒来跟踪移植的人类细胞，使在相对简单和成本效益高的神经性艾滋病毒体内模型中测试新的治疗和病毒跟踪策略成为可能。我们的小鼠模型是在单细胞水平上研究中枢神经系统(CNS)人类免疫缺陷病毒1型(HIV-1)感染和潜伏的遗传机制的有力工具。我们模型的一个主要优势是它使用了诱导的多能干细胞来源的小胶质细胞，这使得可以在体内探索包括基因功能和治疗性基因操作在内的人类遗传学，这对于用目前基于造血干细胞的神经HIV模型进行研究更具挑战性。我们对异种移植人类细胞的转基因追踪将提供一种定量媒介，以开发减少HIV-1潜伏库的新分子和表观遗传学策略，并测试治疗性炎症靶向药物干预对CNS HIV-1潜伏期的影响。
The central nervous system (CNS) is a major human immunodeficiency virus type-1 (HIV-1) reservoir. Microglia are the primary target cell of HIV-1 infection in the CNS. Current models have not allowed the precise molecular pathways of acute and chronic CNS microglial infection to be tested with in vivo genetic methods. Here, we describe a novel-humanized mouse model utilizing human induced pluripotent stem cell (iPSC)-derived microglia to xenograft into murine hosts. These mice are additionally engrafted with human peripheral blood mononuclear cells that serve as a medium to establish a peripheral infection that then spreads to the CNS microglia xenograft, modeling a trans-blood-brain barrier route of acute CNS HIV-1 infection with human target cells. The approach is compatible with iPSC genetic engineering, including inserting targeted transgenic reporter cassettes to track the xenografted human cells, enabling the testing of novel treatment and viral tracking strategies in a comparatively simple and cost-effective in vivo model for neuroHIV. Our mouse model is a powerful tool for investigating the genetic mechanisms governing central nervous system (CNS) human immunodeficiency virus type-1 (HIV-1) infection and latency in the CNS at a single-cell level. A major advantage of our model is that it uses induced pluripotent stem cell-derived microglia, which enables human genetics, including gene function and therapeutic gene manipulation, to be explored in vivo, which is more challenging to study with current hematopoietic stem cell-based models for neuroHIV. Our transgenic tracing of xenografted human cells will provide a quantitative medium to develop new molecular and epigenetic strategies for reducing the HIV-1 latent reservoir and to test the impact of therapeutic inflammation-targeting drug interventions on CNS HIV-1 latency.
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DOI：
10.1073/pnas.97.22.11984
发表时间：
2000-10-24
影响因子：
11.1
作者：
Baird, GS;Zacharias, DA;Tsien, RY
通讯作者：
Tsien, RY
影响因子：
3.2
作者：
Llewellyn GN;Alvarez-Carbonell D;Chateau M;Karn J;Cannon PM
通讯作者：
Cannon PM
影响因子：
6
作者：
通讯作者：
--
影响因子：
16.2
作者：
Abud EM;Ramirez RN;Martinez ES;Healy LM;Nguyen CHH;Newman SA;Yeromin AV;Scarfone VM;Marsh SE;Fimbres C;Caraway CA;Fote GM;Madany AM;Agrawal A;Kayed R;Gylys KH;Cahalan MD;Cummings BJ;Antel JP;Mortazavi A;Carson MJ;Poon WW;Blurton-Jones M
通讯作者：
Blurton-Jones M
影响因子：
5.4
作者：
Durham, Natasha D.;Chen, Benjamin K.
通讯作者：
Chen, Benjamin K.