Humanized Mice as a Tool to Monitor HIV Brain Reservoirs and Effects of Substance Abuse

 描述：联合抗逆转录病毒疗法(CART)，无论多么有效，都不能消除其淋巴和脑储存库中的病毒感染。血脑屏障是一个实质性的挑战，因为药物的渗透往往受到阻碍。此外，病毒脑库的地点和范围尚未确定。这项提议寻求资金，以建立一个人源化的小鼠模型，以监测在血液淋巴和中枢神经系统隔间以及免疫和非免疫细胞(如星形胶质细胞)中艾滋病毒储存库的形成。在大脑中集中使用携带人类血液和神经胶质细胞的小鼠，使其在人类身上的适用性成为问题。反过来，我们正在开发一种资源，该资源将产生改进的动物模型，以研究人类神经胶质细胞在HIV感染期间与外周免疫的相互作用。双人化小鼠将被验证为研究滥用物质对艾滋病毒中枢神经系统储存库形成和根除的影响的工具。我们改进现有人源化小鼠模型的目标如下：R21期-1)移植人星形胶质细胞并确认其在体内中枢神经系统HIV储库中的作用；2)通过转基因表达人IL-34来增强人先天免疫细胞的发育和功能，并评估细胞因子在HIV-1储库形成中的作用。R33阶段-1)探索滥用物质对中枢神经系统储存库的形成和通过新的抗逆转录病毒方法清除的影响。

 DESCRIPTION: Combination antiretroviral therapy (cART), no matter how effective, cannot eliminate viral infection from its lymphoid and brain reservoirs. The blood-brain-barrier presents a substantive challenge as drug penetrance is often impeded. Moreover, the locale and extent of the viral brain reservoir has yet to be defined. This proposal seeks funds to establish a humanized mouse model to monitor formation of HIV reservoirs in hemato-lymphoid and CNS compartments, and in immune and non-immune cells (such as astrocytes). The focused use of mice carrying human blood and glia in the brain makes applicability to humans problematic. In turn, we are developing a resource that will generate improved animal models to study human glial cells interaction with peripheral immunity during HIV infection. Double humanized mice will be validated as a tool to study effects of substances of abuse on HIV CNS reservoir formation and eradication. Our goals to improve existing humanized mice models are as follows: R21 phase - 1) engraft human astrocytes and confirm their role in CNS HIV reservoir in vivo; and 2) enhance the development and function of human innate immune cells by transgenic expression of human IL-34 and assess cytokine effects on HIV-1 reservoir formation. R33 phase - 1) explore the effects of substances of abuse on formation of CNS reservoir and clearance by new antiretroviral approaches.