CSF & Blood Exosomal microRNAs, Immune Responses, and HAND in ART Suppressed HIV

脑脊液

• 批准号: 9264601
• 负责人: BRINDA EMU
• 金额: $ 20.87万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-19 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9264601
• 关键词: AIDS Dementia Complex; Address; Age; Anti-Retroviral Agents; Apoptosis; Archives; Blood; Body Fluids; Brain; CD8B1 gene; Cell Proliferation; Cells; Central Nervous System Infections; Cerebrospinal Fluid; Chronic; Clinical; Data; Detection; Disease; Disease Progression; Encephalitis; Etiology; Event; Exocytosis; Flow Cytometry; Functional disorder; Future; Gene Expression; Genetic Transcription; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Human; Human Volunteers; Image; Immune; Immune response; Immunologic Markers; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interdisciplinary Study; Intervention; Knowledge; Laboratories; Link; Lipid Bilayers; Lipids; Malignant Neoplasms; Measures; Mediating; Membrane; Messenger RNA; MicroRNAs; Molecular; Molecular Target; Neuraxis; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurologic Dysfunctions; Neuronal Injury; Neuropsychological Tests; Neuropsychology; Outcome; Participant; Pathogenesis; Pattern; Performance; Phenotype; Pilot Projects; Play; Primary Infection; Process; Proteins; RNA; Regimen; Research; Role; Sampling; Source; Specimen; Structure of choroid plexus; Substance abuse problem; T-Lymphocyte; Technology; Tissues; Translations; Untranslated RNA; Viral; antiretroviral therapy; deep sequencing; design; exhaustion; exosome; human subject; immune activation; improved; inflammatory marker; insight; monocyte; nanovesicle; novel; novel marker; performance tests; prevent; public health relevance

 DESCRIPTION (provided by applicant): Despite extensive clinical, laboratory, and imaging evidence that the central nervous system (CNS) is persistently abnormal in some HIV-infected individuals with systemic viral suppression on combination antiretroviral therapy (cART), the underlying mechanisms of this perturbation are poorly understood, including etiologies, cells and tissues involved, and relation to potential persistence of HIV. In an era of increasing global access to cART, defining perturbations of the CNS on sustained cART and identifying potential interventions is the most salient neurologic issue for the 35 million people currently living worldwide with HIV. The current pilot project exploits recognition of the role of exosomal micro-RNAs (exo-miRNA) in disease pathogenesis to further our understanding of the processes underlying HIV related CNS abnormality detected on long-term suppressive cART. Exosomes are membrane nanovesicles released via exocytosis of donor cells that contain small non-coding miRNAs (exo-miRNAs) that regulate gene expression in target cells. Exo-miRNAs play important roles in disease pathogenesis including regulating immune responses in target tissues. Furthermore, viral exo- miRNAs may reveal HIV persistence, and other specific exo-miRNAs indicate cellular origins. To examine the associations between exo-miRNA in the CNS and cART treated HIV, in Aim 1 we will cross-sectionally profile exo-miRNA in cerebrospinal fluid (CSF) and blood by deep sequencing in individuals on sustained cART and HIV-uninfected comparison study participants. We hypothesize that CSF exo-miRNA associated with inflammation will be more abundant in cART-suppressed participants and that CSF exo-miRNAs will be enriched for inflammatory-mediating miRNAs compared to blood. We will explore whether HIV-derived exo-miRNAs can be detected in CSF, suggesting HIV persistence, and the impact of early versus later initiation of cART on exo-miRNA profiles. In Aim 2 we will investigate the mechanistic relationships between exo-miRNA profiles, immune activation and exhaustion in the CNS and blood, and neurocognitive performance. We hypothesize that in CSF and blood, exo-miRNAs linked to inflammation will correlate with activation of monocytes and T lymphocytes as measured by flow cytometry and soluble markers of immune activation, and that poorer neuropsychological testing performance will associate with inflammatory profiles of miRNA in CSF. Our long-term goal is to provide improved understanding of the causes of CNS perturbation in treated HIV in order to develop targeted adjunctive therapies to ameliorate HIV associated neurocognitive disorder.

 描述（由申请人提供）：尽管大量的临床、实验室和影像学证据表明，在联合抗逆转录病毒疗法（cART）进行全身病毒抑制的一些 HIV 感染者中，中枢神经系统（CNS）持续异常，但这种情况的潜在机制人们对扰动的了解知之甚少，包括病因、涉及的细胞和组织，以及与艾滋病毒潜在持续存在的关系。对于目前全球 3500 万艾滋病毒感染者来说，这是最突出的神经系统问题。当前的试点项目利用对外泌体微小 RNA (exo-miRNA) 在疾病发病机制中的作用的认识，以进一步了解艾滋病毒相关中枢神经系统异常的潜在过程。在长期抑制性 cART 中检测到的外泌体是通过供体细胞的胞吐作用释放的膜纳米囊泡，其中含有调节靶标基因表达的小非编码 miRNA (exo-miRNA)。 Exo-miRNA 在疾病发病机制中发挥重要作用，包括调节靶组织的免疫反应，此外，病毒 exo-miRNA 可能揭示 HIV 的持久性，而其他特定的 exo-miRNA 则表明细胞起源。 CNS 和 cART 治疗 HIV，在目标 1 中，我们将通过对持续 cART 和未感染 HIV 的比较研究参与者的个体进行深度测序，对脑脊液 (CSF) 和血液中的 exo-miRNA 进行横断面分析。与血液相关的 CSF exo-miRNA 在 cART 抑制的参与者中会更加丰富，并且与血液相比，CSF exo-miRNA 将富集炎症介导的 miRNA。我们将探索是否可以在 CSF 中检测到 HIV 衍生的 exo-miRNA。 ，表明 HIV 持续存在，以及早期与晚期开始 cART 对 exo-miRNA 图谱的影响。在目标 2 中，我们将研究中枢神经系统中 exo-miRNA 图谱、免疫激活和耗竭之间的机制关系。我们发现，在脑脊液和血液中，与炎症相关的外切 miRNA 将与通过流式细胞术和可溶性免疫激活标记物测量的单核细胞和 T 淋巴细胞的激活相关，并且较差的神经心理学测试表现将与单核细胞和 T 淋巴细胞的激活相关。我们的长期目标是更好地了解治疗 HIV 的中枢神经系统紊乱的原因，以便开发有针对性的辅助疗法来改善 HIV 相关的神经认知功能。紊乱。