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

• 批准号: 10305639
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305639
• 关键词: Acute; Address; Adult; Animal Model; Animals; Anti-Retroviral Agents; Astrocytes; Astrocytoma; Brain; Cell Line; Cells; Clinical; DNA; Detection; Disease; Effectiveness; Evolution; Glial Fibrillary Acidic Protein; HIV; HIV Infections; HIV-associated neurocognitive disorder; Home; Human; Immune; Infection; Inflammatory Response; Invaded; Mediating; Modeling; Mus; Organ; Penetration; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Population; Process; RNA; Role; Seeds; 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; macrophage; mature animal; mouse model; neglect; neonate; novel; pressure; reconstitution; targeted treatment; trafficking

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 在疾病的急性阶段，为炎症反应奠定了基础，最终导致临床症状 HIV相关神经认知障碍（HAND）的表现。尚不清楚是否长期感染 脑细胞释放出高效的病毒，这些病毒可以从大脑中逸出，重新播种到周围器官。星形胶质细胞是 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。鉴于无法进行侵入性 研究中枢神经系统和星形胶质细胞作为人类艾滋病毒储存库的作用 及其与周围器官的动态相互作用，我们开发了一种嵌合的人星形胶质细胞/人 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 有效的艾滋病毒并将艾滋病毒从大脑驱散到外周。我们证明星形胶质细胞启动 有复制能力的艾滋病毒从大脑传播到脾脏和淋巴结。在这个应用程序中，我们 提议确定 HIV 从大脑转移到外周器官的机制（目标 1）， 评估联合抗逆转录病毒治疗下 HIV 从感染 HIV 的星形胶质细胞到外周器官的 HIV 排出 (cART)（目标 2），并评估大脑内以及大脑与周围器官之间的病毒进化 时间（目标 3）。总的来说，我们的研究将建立范式转变并更好地理解动态 HIV在大脑和周围器官之间的相互作用，可以为新型中枢神经系统靶向治疗提供信息 干预措施。