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

基本信息

批准号：
10610954
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
项目类别：
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/10610954
关键词：
Accounting Address Aftercare Altruism Anti-Retroviral Agents Autopsy Basal Ganglia Binding Biological Assay Blood Blood - brain barrier anatomy Brain Brain Injuries CD86 gene Cd68 Cell Death Cell Death Signaling Process Cell Density Cell Separation Cell physiology Cells Central Nervous System 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 Human IL18 gene ITGAX gene Immune response Inflammasome Inflammation Inflammatory Interleukin-1 beta Interruption Intervention Knowledge Length Linear Models Literature Macrophage Maintenance Maps Measures Microglia Modeling Modernization Myeloid Cell Activation Myeloid Cells Nervous System Trauma Neurocognitive Neurons Opioid Organ Parents Participant Pathway interactions Pattern Recognition Pattern recognition receptor Penetration Peripheral Persons Pharmaceutical Preparations Phenotype Population Predisposition Process Proviruses RIPK1 gene RNA Residual state Rest Role Site Sorting 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 migration neuroinflammation opioid exposure opioid use participant enrollment pharmacologic prescription opioid protein expression single-cell RNA sequencing trafficking trait transcriptomics transmission process white matter

项目摘要

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.

概括 HIV在传播后尽快感染大脑，但尚不清楚感染的脑细胞如何促进HIV 持久性以及这些细胞是否会释放出可以在大脑外种子细胞的可行病毒。还不清楚尽管炎症和外部因素（例如抗逆转录病毒），HIV持续性如何导致局部细胞损伤 [ARV]穿透和阿片类药物）可能会影响这种损害。这种新知识对于艾滋病毒治愈可能很重要艾滋病毒（PWH）患者改善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，骨髓细胞在持久性和消除大脑HIV-1储层，作者：（i）绘制HIV储层大小，组成和活动脑髓样细胞（BMC）与细胞密度以及ARV和阿片类药物的水平有关，（ii）确定作用在ARV的环境中治疗（ART）和治疗后中断，以及（iii）定义BMC中HIV储量的大小和活动的方式与局部炎症和细胞损伤有关。我们的目标是检查BMC在HIV持久性，局部炎症引起的损害以及作为来源的作用可以从中枢神经系统流出到重种外围器官的病毒。该项目的基本原理得到了文献的支持，表明大脑巨噬细胞和小胶质细胞可以在现代艺术期间持续存在的港口艾滋病毒。这些巨噬细胞和小胶质细胞的营业额较低（来自几个月到几年）使它们成为艾滋病毒的独特水库。而静息T细胞中的HIV已广泛特征是，BMC作为停止艺术的反弹来源的作用尚未确定。更远， BMC中的艾滋病毒也可能触发免疫反应，即使在ART期间也会造成局部损害。我们的总体假设是，BMC（主要是小胶质细胞）有助于CNS中的HIV持续性区域异质性。在这些BMC中携带的艾滋病毒也可能导致炎症相关的脑损伤并在停止艺术时会导致病毒分散。我们还假设艾滋病毒持续性，局部损害病毒分散受到局部ARV和阿片类药物水平的影响。为了解决这些开放的问题，我们的研究将收集和分析整个中枢神经系统的组织（白色和灰色额叶皮层，丘脑，海马，基底神经节，小脑，脊髓），回肠，脾脏，血液和脑脊液（CSF）的无私PWH的脑脊液（CSF）参加了最后一项持续的快速尸检研究。一些参与者（n = 15）将一直在病毒抑制直到死亡，而另一些参与者（n = 5）则希望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PWH很重要，因为它们将为制定策略提供新的见解清除HIV感染并减少炎症依赖性小胶质细胞诱导的神经系统损害。