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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

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大量证据表明，艾滋病毒会感染大脑。在疾病的急性期，为炎症反应奠定基础，最终导致临床 HIV相关神经认知障碍的表现(手)。目前尚不清楚长寿的感染者是否脑细胞释放高产病毒，这些病毒可以从大脑中流出，重新播种外围器官。星形胶质细胞大脑中的主要细胞类型，虽然它们抵抗艾滋病毒融合，但它们可以支持艾滋病毒进入替代机制，以及艾滋病毒整合和潜伏艾滋病毒的重新激活。考虑到无法入侵研究一般情况下中枢神经系统，特别是星形胶质细胞在人类体内作为HIV储存库的作用及其与周围器官的动态相互作用，我们开发了人星形胶质细胞/人嵌合体外周血单核细胞小鼠模型研究星形胶质细胞在复制中的作用它能够有效地控制艾滋病毒的传播，并将艾滋病毒从大脑扩散到外周。我们展示了星形胶质细胞发起的具有复制能力的艾滋病毒从大脑传播到脾和淋巴结。在此应用程序中，我们提议确定艾滋病毒从大脑进入外周器官的机制(目标1)，评估联合抗逆转录病毒治疗下HIV感染星形胶质细胞向外周器官的HIV外流 (CART)(目标2)，并评估病毒在大脑内以及大脑和周围器官之间的进化时间(目标3)。总体而言，我们的研究将建立一种范式转变，并更好地理解动态 HIV在脑和外周器官之间的相互作用，可以提供新的中枢神经系统靶向治疗干预措施。