Dynamic interaction between HIV in the CNS and peripheral organs

HIV在中枢神经系统和周围器官中的动态相互作用

基本信息

批准号：
10524054
负责人：
Lena Al-Harthi
金额：
$ 73.87万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10524054
关键词：
Acute Address Adult Animal Model Animals Anti-Retroviral Agents Astrocytes Astrocytoma Brain Cell Line Cells Clinical DNA Detection Disease Effectiveness Engraftment Evolution Glial Fibrillary Acidic Protein HIV HIV Infections HIV-associated neurocognitive disorder Home Human Immune Infection Inflammatory Response Invaded Knockout Mice Macrophage Mediating Modeling Organ Penetration Peripheral Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Population Process Productivity RNA Replication Initiation Role Site Spleen T-Lymphocyte Techniques Testing Therapeutic Intervention Time Tissues Transplantation Viral Virus antiretroviral therapy brain cell cell type deep sequencing fetal in vivo indexing lymph nodes migration mouse model neglect neonate novel pressure reactivation from latency reconstitution targeted treatment trafficking

Acute Address Adult Animal Model Animals Anti-Retroviral Agents Astrocytes Astrocytoma Brain Cell Line Cells Clinical DNA Detection Disease Effectiveness Engraftment Evolution Glial Fibrillary Acidic Protein HIV HIV Infections HIV-associated neurocognitive disorder Home Human Immune Infection Inflammatory Response Invaded Knockout Mice Macrophage Mediating Modeling Organ Penetration Peripheral Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Population Process Productivity RNA Replication Initiation Role Site Spleen T-Lymphocyte Techniques Testing Therapeutic Intervention Time Tissues Transplantation Viral Virus antiretroviral therapy brain cell cell type deep sequencing fetal in vivo indexing lymph nodes migration mouse model neglect neonate novel pressure reactivation from latency reconstitution targeted treatment trafficking

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项目摘要

Abstract: Ample evidence from animal and human studies demonstrate that HIV infects the brain during acute stage of the disease, setting the stage for inflammatory responses culminating in a clinical manifestation of HIV-Associated Neurocognitive Disorders (HAND). It is unknown whether long lived-infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs. Astrocytes are the predominate cell type in the brain and while they resist HIV fusion, they can support HIV entry though alternative mechanisms, and HIV integration and re-activation of latent HIV. Given the inability for invasive studies to examine the role of the CNS in general and astrocytes in particular as a reservoir for HIV in humans and its dynamic interaction with peripheral organs, we developed a chimeric human astrocyte/human peripheral blood mononuclear cell mouse model to address the role of astrocytes in harboring replication competent HIV and in dissipating HIV from the brain to the periphery. We demonstrate astrocyte-initiated replication competent HIV spread from the brain to the spleen and lymph nodes. In this application, we propose to determine the mechanism by which HIV egress from the brain to peripheral organs (Aim 1), evaluate HIV egress from HIV infected astrocytes to peripheral organs under combination antiretroviral therapy (cART) (Aim 2), and assess viral evolution within the brain and between the brain and peripheral organs over time (Aim 3). Collectively our studies will establish a paradigm shift and a greater understanding of the dynamic interaction of HIV between the brain and peripheral organs, which can inform novel CNS-targeted therapeutic interventions.

摘要：来自动物和人类研究的充分证据表明HIV感染了大脑在疾病的急性阶段，为临床上的炎症反应奠定了基础与HIV相关的神经认知障碍的表现（手）。尚不清楚长期感染了脑细胞释放可以从大脑出口到再种子外围器官的生产性病毒。星形胶质细胞是大脑中的主要细胞类型，在抵抗HIV融合时，它们可以支持HIV进入潜在艾滋病毒的替代机制以及HIV整合和重新激活。鉴于无法入侵研究中枢神经系统在一般和星形胶质细胞中的作用，尤其是作为人类艾滋病毒的水库以及它与外围器官的动态相互作用，我们开发了一个嵌合的人星形细胞/人类外周血单核细胞小鼠模型，以解决星形胶质细胞在复制中的作用有能力的艾滋病毒和艾滋病毒从大脑散发到周围的艾滋病毒。我们展示了星形胶质细胞的发射复制能干的HIV从大脑传播到脾脏和淋巴结。在此应用程序中，我们建议确定艾滋病毒从大脑流向周围器官的机制（AIM 1），在组合抗逆转录病毒疗法下评估来自HIV感染的星形胶质细胞到外围器官的HIV出口（购物车）（AIM 2），并评估大脑内以及大脑和周围器官之间的病毒演化时间（目标3）。我们的研究集体将建立范式转变，并对动态有更深入的了解艾滋病毒在大脑和外围器官之间的相互作用，这可以告知新型CNS靶向治疗干预措施。