Integrative Modeling of HIV-Associated Neurocognitive Disorder in Human Brain Organoids

人脑类器官中 HIV 相关神经认知障碍的综合建模

• 批准号: 10055749
• 负责人: Oliver I Fregoso
• 金额: $ 61.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10055749
• 关键词: 3-Dimensional; AIDS dementia; Acquired Immunodeficiency Syndrome; Acute; Affect; Astrocytes; Autopsy; Biological Assay; Biology; Brain; Cell Culture System; Cell Nucleus; Cells; Cessation of life; Chronic; Consequences of HIV; Development; Disease; Drug usage; Epidemic; Face; Foundations; Functional Imaging; Gene Expression; Genetic Transcription; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Health; Heroin; Histopathology; Human; Immune; Immune response; Immune signaling; Individual; Infection; Inflammation; Innate Immune Response; Intravenous; Knowledge; Measures; Microglia; Modeling; Molecular; Monitor; Myeloid Cells; Nerve Degeneration; Neural Network Simulation; Neurocognitive; Neurocognitive Deficit; Neurons; Neurophysiology - biologic function; Neuroprotective Agents; Opioid; Organoids; Pathology; Patients; Pharmaceutical Preparations; Plant Roots; Play; Population; Preclinical Testing; Quality of life; Research; Role; Signal Transduction; Structure; Synapses; System; Systems Analysis; Testing; Therapeutic; Time; Tissues; Translating; Unmarried person; Viral Load result; acute infection; antiretroviral therapy; chronic infection; cytokine; experience; human pluripotent stem cell; human stem cells; human tissue; immune activation; in vitro Model; innovation; insight; method development; monocyte; nervous system disorder; neural network; neurocognitive disorder; neuroinflammation; neuropathology; new therapeutic target; prescription opioid abuse; relating to nervous system; response; stem cell technology; success

PROJECT SUMMARY Approximately 40 million people are currently infected by HIV, with an additional 1.7 million people newly infected each year. While only a single person has been functionally cured of HIV, advances in antiretroviral therapy (ART) have drastically decreased AIDS-related illnesses and deaths for individuals on ART. However, HIV+ patients on ART still face debilitating AIDS-independent diseases, including HIV-associated neurocognitive disorders (HAND). HAND refers to a spectrum of three neurocognitive disorders that influence survival, quality of life, and everyday function: asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). While the number of patients with the more severe forms of HAND have declined since the introduction of ART, an estimated 15-55% of HIV+ patients taking ART still develop a neurocognitive disorder. Patients with ANI are two to six times more likely to progress to a more severe form of HAND when compared to HIV+ patients who are neurocognitively normal. Thus, HAND remains an important and prevalent HIV-associated disease to affect individuals in the ART era. It is now thought that HAND develops because of functional changes in neurons caused by chronic inflammation and HIV infection of an immune cell in the brain, microglia. Though they are not a neuronal cell, microglia do play an important role in the general health and function of neural tissue. The immune responses of microglia are thought to be tightly regulated and controlled as to not normally harm the surrounding neurons. We do know that HIV can infect microglia. However, little is known about the progression of acute and chronic HIV infection in microglia nor how and what impact these infected cells have on surrounding neuronal tissue. Moreover, HIV infection is frequently associated with intravenous drug us such as heroin along with the growing abuse of prescription opioids. It remains unclear how the use of these drugs alters both neuronal and innate immune signaling and further contributes to HAND. One major roadblock in understanding infection of microglia has been the lack of systems for analysis in culture, as well as means for studying their impact on human brain functions. Recent developments in human pluripotent stem cell (hPSC)-derived microglia and 3D-brain organoids have opened new doors to understand HIV infection in these otherwise intractable cells. We have begun to bridge this knowledge gap by leveraging our strengths in HIV and brain organoid biology to model HAND in culture, where we can finally begin to answer important questions in the roles of HIV, opioids, and microglia and other cells in this debilitating HIV- associated disease. Success of our proposed research will 1) define the response of microglia to HIV infection and opioid treatment, 2) characterize how dysregulated microglia affect brain organoid structure, neural network health, and signaling, and 3) establish a foundation for therapeutic discovery to reduce neuroinflammation and HAND.

项目摘要 目前约有4 000万人感染艾滋病毒，另有170万人是新感染者。 每年感染。虽然只有一个人的艾滋病毒得到功能性治愈，但抗逆转录病毒药物的进展 抗逆转录病毒疗法（ART）大大减少了接受ART治疗的个人的艾滋病相关疾病和死亡。然而， 接受抗逆转录病毒疗法的艾滋病毒阳性患者仍然面临着使人衰弱的非艾滋病依赖性疾病，包括艾滋病毒相关疾病。 神经认知障碍（HAND）。HAND指的是一系列的三种神经认知障碍， 生存率、生活质量和日常功能：无症状神经认知功能障碍（ANI），轻度 神经认知障碍（MND）和HIV相关痴呆（HAD）。虽然患者人数 自抗逆转录病毒疗法引入以来，更严重的HAND形式有所下降，估计15-55%的HIV+ 接受抗逆转录病毒治疗的患者仍然会出现神经认知障碍。ANI患者发生以下情况的可能性是正常人的2 - 6倍： 与神经认知正常的HIV+患者相比，HIV+患者进展为更严重的HAND形式。 因此，在ART时代，HAND仍然是影响个体的重要和流行的HIV相关疾病。 现在人们认为，HAND的形成是由于慢性炎症引起的神经元功能变化造成的 炎症和艾滋病毒感染的免疫细胞在大脑中，小胶质细胞。虽然它们不是神经细胞， 小胶质细胞在神经组织的一般健康和功能中发挥重要作用。的免疫应答 小胶质细胞被认为受到严格的调节和控制，通常不会伤害周围的神经元。 我们知道艾滋病毒可以感染小胶质细胞。然而，关于急性和慢性的进展知之甚少。 小胶质细胞中的HIV感染也不知道这些受感染的细胞如何以及如何影响周围的神经元组织。 此外，艾滋病毒感染经常与静脉注射毒品有关，如海洛因沿着 滥用处方阿片类药物的现象日益严重。目前尚不清楚这些药物的使用如何改变神经元和 先天免疫信号传导，并进一步有助于HAND。 理解小胶质细胞感染的一个主要障碍是缺乏分析系统， 文化，以及研究它们对人类大脑功能影响的手段。人类的最新发展 多能干细胞（hPSC）衍生的小胶质细胞和3D脑类器官为理解 艾滋病毒感染在这些细胞中，否则难以处理。我们已经开始弥合这一知识差距， 我们在HIV和脑类器官生物学方面的优势，在培养中模拟HAND，我们终于可以开始 回答艾滋病毒，阿片类药物，小胶质细胞和其他细胞在这种削弱艾滋病毒中的作用的重要问题- 相关疾病。我们所提议的研究的成功将1）定义小胶质细胞对HIV感染的反应 和阿片类药物治疗，2）表征失调的小胶质细胞如何影响脑类器官结构，神经 网络健康和信号，以及3）建立治疗发现的基础，以减少 神经炎症和手。