Decoding epigenetic scars of smoldering neuroinflammation and CNS complications in people with HIV

解码艾滋病毒感染者闷烧性神经炎症和中枢神经系统并发症的表观遗传疤痕

• 批准号: 10748566
• 负责人: Michael Jay Corley
• 金额: $ 102.36万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748566
• 关键词: 3-Dimensional; Abnormal Myeloid Cell; Acute; Automobile Driving; Autopsy; Biological; Biological Assay; Biological Markers; Blood; Brain; Brain region; CD8B1 gene; Cell Nucleus; Cell physiology; Cells; Cellular Assay; Central Nervous System; Cerebrospinal Fluid; Chromatin; Cicatrix; Clinical; Cognition; Cognitive; Cohort Studies; Congenital neurologic anomalies; DNA; DNA Methylation; DNA Modification Process; Disease; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; HIV; HIV Infections; HIV-1; HIV-associated cognitive impairment; Health; IL6 gene; Immune; Immune system; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-1 beta; Intervention; Link; Longevity; Machine Learning; Mediating; Mediator; Memory; Microglia; Molecular; Myelogenous; Myeloid Cell Activation; Myeloid Cells; NR4A2 gene; National NeuroAids Tissue Consortium; Nervous System Trauma; Neuroglia; Neuroimmune; Neurologic; Neuronal Injury; Nucleic Acid Regulatory Sequences; Outcome; Participant; Pathway interactions; Performance; Persons; Population; Proteins; Protocols documentation; Publishing; RNA; Regulator Genes; Research; Resolution; Role; Sensorimotor functions; Short-Term Memory; Specimen; Spinal Puncture; Structure of choroid plexus; Syndrome; T memory cell; T-Lymphocyte; TNF gene; Technology; Testing; Therapeutically Targetable; Time; Tissues; Ventricular; Viral; Viral Pathogenesis; Virus Replication; Work; antiretroviral therapy; biotypes; brain tissue; cell type; cognitive control; cognitive function; cognitive testing; comorbidity; epigenetic marker; epigenome; experience; gene network; glial activation; histone modification; immune activation; in vivo; inflammatory marker; innovation; lens; multimodality; multiple omics; neuroinflammation; novel; novel therapeutics; prevent; programs; protein expression; single cell analysis; success; transcriptomics

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to unravel mechanisms driving abnormal immune activation and cognitive impairment in people living with HIV (PLWH) through the lens of epigenetic programming. Despite overall advances in lifespan and health for PLWH who are on suppressive ART, a subset of individuals on ART continue to demonstrate neuroimmune abnormalities and associated clinical neurological syndromes including cognitive complications. Cerebrospinal fluid (CSF) studies are a window into the CNS of PLWH, revealing a role for abnormal myeloid cell activation and persistence viral replication in the CNS, despite apparent systemic viral suppression with ART. Our own single cell genomic studies of fresh CSF cells from PLWH have shown that a rare microglia-like myeloid cell population resides in the CSF in PLWH; that these cells are linked to HIV disease status; and that these myeloid cells can harbor HIV DNA. Additionally, our research has shown that epigenetic features of myeloid cells are rapidly altered in HIV infection and this aberrant myeloid epigenetic state associated with HIV infection persists despite the immediate initiation of ART during acute HIV infection. However, despite myeloid cells being recognized as crucial cellular mediators of CNS abnormalities in PLWH, the epigenetic landscapes of CNS myeloid and other immune cells in PLWH remain uncharted. Our central hypothesis is that HIV leaves epigenetic “scars” at regulatory regions of proinflammatory gene networks in distinct CSF myeloid cell subsets, contributing to HIV-related cognitive impairment despite ART. This hypothesis will be tested in our established HIV Associated Reservoirs and Comorbidities Study (HARC) cohort at Yale that includes large volume lumbar puncture from study participants with and without HIV and will be further explored utilizing postmortem brain specimens from the National NeuroAIDS Tissue Consortium (NNTC). In PLWH, we will longitudinally assess fresh CSF myeloid and T cell single cell epigenetic and transcriptional cell states over the course of ART treatment and ask whether there is damage to the epigenomes of CSF myeloid and T cells sustained during HIV infection that persists over time as epigenetic “scars”. Using machine learning, we will then assess for an association between epigenetic perturbations in PLWH and CNS outcomes, including cognitive impairment and abnormal CSF soluble biomarkers of inflammation and neuronal injury. We will also explore single cell epigenetic cell states of myeloid and glia in postmortem brain tissues from choroid plexus and periventricular zones of HIV-infected individuals who died on suppressive ART and matched controls. Lastly, we will apply an innovative new single cell assay for multifactorial chromatin profiling to assay histone modifications. These proposed, in-depth, multiomic single cell analyses of distinct myeloid cell subsets in the CNS and blood, combined with cognitive assessments, will reveal the effects of HIV infection on immune cell epigenomes, and will uncover transcriptional and epigenetic states most strongly related to cognitive complications in PLWH. The results will advance efforts to biotype CNS complications in PLWH based on immune and viral pathogenesis.

项目总结/摘要 这项提案的目标是解开驱动异常免疫激活和认知障碍的机制 通过表观遗传编程的透镜，尽管总体上取得了进展， 对于正在接受抑制性抗逆转录病毒疗法的艾滋病毒携带者， 表现出神经免疫异常和相关的临床神经系统综合征，包括认知 并发症脑脊液（CSF）研究是了解PLWH中枢神经系统的一个窗口，揭示了 尽管存在明显的全身性病毒感染， 我们自己对PLWH新鲜CSF细胞的单细胞基因组研究表明， 一种罕见的小胶质细胞样骨髓细胞群存在于PLWH的CSF中;这些细胞与HIV疾病有关 这些骨髓细胞可以携带HIV DNA。此外，我们的研究表明，表观遗传 在HIV感染中，髓系细胞的特征迅速改变，这种异常的髓系表观遗传状态与 尽管在急性HIV感染期间立即开始ART，但HIV感染仍然存在。但尽管 髓系细胞被认为是PLWH中CNS异常的关键细胞介质，表观遗传 PLWH中CNS髓样细胞和其他免疫细胞的情况仍然未知。我们的核心假设是 HIV在不同的组织中的促炎基因网络的调节区域留下了表观遗传“疤痕”， CSF髓样细胞亚群，尽管ART，仍会导致HIV相关的认知障碍。 将在我们在耶鲁大学建立的HIV相关储库和合并症研究（HARC）队列中进行测试， 包括来自有和没有HIV的研究参与者的大容量腰椎穿刺，并将进一步探讨 使用来自国家神经艾滋病组织联盟（NNTC）的死后脑标本。在PLWH，我们 将纵向评估新鲜CSF骨髓和T细胞单细胞表观遗传和转录细胞状态， ART治疗的过程，并询问CSF髓细胞和T细胞的表观基因组是否有损伤 在艾滋病毒感染期间持续存在，随着时间的推移作为表观遗传“疤痕”持续存在。通过机器学习，我们将 评估PLWH的表观遗传扰动与CNS结局之间的关联，包括认知功能 炎症和神经元损伤的损害和异常CSF可溶性生物标志物。我们还将探索 死后脉络丛脑组织中髓样和胶质细胞的单细胞表观遗传细胞状态， 在抑制性抗逆转录病毒治疗中死亡的HIV感染者和匹配的对照者的脑室周围区。最后我们 将应用一种创新的新的单细胞检测多因子染色质分析，以测定组蛋白修饰。 这些提议对中枢神经系统和血液中不同的骨髓细胞亚群进行深入的多组单细胞分析， 结合认知评估，将揭示艾滋病毒感染对免疫细胞表观基因组的影响， 将揭示与PLWH认知并发症密切相关的转录和表观遗传状态。的 研究结果将推进基于免疫和病毒发病机制的PLWH CNS并发症生物分型的努力。