Brain Myeloid Cells are Sources of HIV-associated Damage and Viral Dispersal

脑髓细胞是 HIV 相关损伤和病毒传播的来源

• 批准号: 10445308
• 负责人: Antoine Chaillon
• 金额: $ 70.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445308
• 关键词: Accounting; Address; Aftercare; Altruism; Anti-Retroviral Agents; Autopsy; Basal Ganglia; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; Brain Injuries; CD86 gene; Cell Death; Cell Death Signaling Process; Cell Density; Cell physiology; Cells; Cerebellum; Cerebrospinal Fluid; Cessation of life; Characteristics; Clonal Expansion; Consequences of HIV; DNA; Data; Development; Enrollment; Event; Gene Expression; Genes; Genetic Transcription; Gifts; Goals; HIV; HIV Infections; HIV-1; Heterogeneity; Hippocampus (Brain); Human; ITGAX gene; Immune response; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-18; Interruption; Intervention; Knowledge; Length; Linear Models; Literature; Maintenance; Maps; Measures; Microglia; Modeling; Modernization; Myeloid Cell Activation; Myeloid Cells; Nervous System Trauma; Neuraxis; Neurocognitive; Neurons; Opioid; Organ; Parents; Participant; Pathway interactions; Pattern recognition receptor; Penetration; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Process; Proviruses; RIPK1 gene; RNA; Residual state; Rest; Role; Seeds; Site; Source; Spinal Cord; Spleen; T-Lymphocyte; TNF gene; Thalamic structure; Time; Tissues; Viral; Virus; antiretroviral therapy; brain cell; brain health; cell injury; cell motility; cohort; cytokine; density; frontal lobe; genome sequencing; gray matter; ileum; improved; insight; integration site; macrophage; migration; neuroinflammation; opioid exposure; opioid use; prescription opioid; protein expression; single-cell RNA sequencing; trafficking; trait; transcriptomics; transmission process; white matter

SUMMARY HIV infects the brain soon after transmission, but it is unknown how infected brain cells contribute to HIV persistence and whether these cells release viable virus that can seed cells outside the brain. It is also unclear how HIV persistence leads to local cellular damage, although inflammatory and external factors (like antiretroviral [ARV] penetration and opioids) likely impact such damage. Such new knowledge could be important for HIV cure strategies and ways to improve brain health in persons with HIV (PWH). This project will address stated objectives of RFA-MH-20-701, Role of Myeloid Cells in Persistence and Eradication of HIV-1 Reservoirs from the Brain, by: (i) mapping HIV reservoir size, composition, and activity in brain myeloid cells (BMC) in relation to cellular density and levels of ARV and opioids, (ii) determining the role of BMC in HIV dispersal within the central nervous system (CNS) and across the body in the setting of ARV treatment (ART) and after treatment interruption, and (iii) defining how HIV reservoir size and activity in BMC is associated with local inflammation and cell damage. Our goal is to examine the role of BMC in HIV persistence, local inflammatory-induced damage and as a source of viruses that can egress from the CNS to re-seed peripheral organs. The rationale for this project is supported by literature demonstrating that brain macrophages and microglia can harbor HIV that persists during modern ART. The low turnover of these macrophages and microglial cells (from months to years) make them unique reservoirs for HIV. While HIV in resting T cells has been extensively characterized, the role of BMC as a source of rebound upon cessation of ART is yet to be determined. Further, HIV in BMC likely triggers immune responses, even during ART, causing local damage. Our overall hypothesis is that BMC (primarily microglial cells) contribute to HIV persistence in the CNS with regional heterogeneity. HIV harbored in these BMC likely also causes inflammation-associated brain damage and contributes to viral dispersal when ART is stopped. We also hypothesize that HIV persistence, local damage and viral dispersal are influenced by local ARV and opioid levels. To address these open questions, our study will collect and analyze tissues throughout the CNS (white and grey matters of frontal cortex, thalamus, hippocampus, basal ganglia, cerebellum, spinal cord), ileum, spleen, blood and cerebrospinal fluid (CSF) of altruistic PWH enrolled in the Last Gift cohort, an ongoing rapid autopsy study. Some participants (n=15) will remain virally suppressed until the time of death, while others (n=5) will want to stop their ART before death. Half of the population will use prescription opioids. These studies will be important for PWH because they will provide new insights for the development of strategies to clear HIV infection and lessen inflammatory-dependent microglial-induced neurological damage.

摘要 HIV在传播后不久就会感染大脑，但感染的脑细胞如何对HIV起作用尚不清楚 持久性，以及这些细胞是否释放可以在脑外播种细胞的活病毒。目前也不清楚 艾滋病毒的持久性如何导致局部细胞损伤，尽管炎症和外部因素(如抗逆转录病毒 [抗逆转录病毒药物]渗透和阿片类药物)可能会影响这种损害。这些新知识可能对艾滋病毒的治疗很重要 改善艾滋病毒感染者大脑健康的策略和方法。 该项目将解决RFA-MH-20-701的既定目标，髓系细胞在持久性和 从大脑中根除HIV-1储存库，方法是：(I)绘制HIV储存库的大小、组成和活性 脑髓系细胞(BMC)与细胞密度及ARV和阿片类药物水平的关系，(Ii)确定其作用 在ARV的背景下，HIV在中枢神经系统(CNS)内和在全身扩散中的BMC 治疗(ART)和治疗中断后，以及(Iii)确定艾滋病毒储存库的大小和BMC中的活动 与局部炎症和细胞损伤有关。 我们的目标是研究BMC在HIV持续存在、局部炎症诱导的损伤和作为来源的作用 可以从中枢神经系统出来重新播种外周器官的病毒。 这个项目的理论基础得到了文献的支持，这些文献表明，脑巨噬细胞和小胶质细胞可以 怀有在现代艺术中持续存在的艾滋病毒。这些巨噬细胞和小胶质细胞的低周转(从 几个月到几年)使它们成为艾滋病毒的独特储存库。虽然静息T细胞中的艾滋病毒已经广泛存在 在ART停止后，BMC作为反弹来源的作用尚未确定。此外， BMC中的艾滋病毒可能会触发免疫反应，即使在抗逆转录病毒治疗期间也是如此，从而造成局部损害。 我们的总体假设是，骨髓基质细胞(主要是小胶质细胞)有助于HIV在中枢神经系统的持续存在 区域异质性。这些BMC中携带的HIV可能还会导致炎症相关的脑损伤 当ART停止时，有助于病毒的传播。我们还假设艾滋病毒的持久性、局部损害 病毒的传播受局部ARV和阿片类药物水平的影响。 为了解决这些悬而未决的问题，我们的研究将收集和分析整个中枢神经系统(白色和灰色)的组织 额叶皮质、丘脑、海马体、基底节、小脑、脊髓)、回肠、脾、血 无私的PWH的脑脊液(CSF)登记在正在进行的快速尸检研究Last Gift队列中。 一些参与者(n=15)将一直受到病毒抑制，直到死亡，而另一些参与者(n=5)则希望 在死前停止他们的艺术。一半的人口将使用处方阿片类药物。 这些研究对威尔斯亲王医院非常重要，因为它们将为发展策略提供新的见解。 清除HIV感染，减轻炎症依赖的小胶质细胞诱导的神经损伤。