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.

翻译后摘要：从动物和人类研究的充分证据表明，艾滋病毒感染的大脑 在疾病的急性期，为炎症反应奠定基础，最终导致临床 HIV相关的神经认知障碍（HAND）目前尚不清楚是否长期感染 脑细胞释放出大量病毒，这些病毒可以从大脑中排出，重新接种外周器官。星形胶质细胞是 在大脑中占主导地位的细胞类型，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HIV整合和潜伏HIV的重新激活。由于无法侵入 研究检查中枢神经系统的作用，特别是星形胶质细胞作为人类艾滋病毒的储存库 及其与外周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，以解决星形胶质细胞在窝藏复制中的作用 并将艾滋病毒从大脑分散到外周。我们证明了星形胶质细胞启动的 具有复制能力的HIV从大脑扩散到脾脏和淋巴结。在本申请中，我们 建议确定HIV从大脑到外周器官的机制（目标1）， 评价在联合抗逆转录病毒治疗下HIV从HIV感染的星形胶质细胞到外周器官的流出 （cART）（目的2），并评估大脑内以及大脑和外周器官之间的病毒进化， 时间（目标3）。总的来说，我们的研究将建立一个范式转变，并更好地了解动态 HIV在大脑和外周器官之间的相互作用，这可以为新型CNS靶向治疗提供信息。 干预措施。