Defining brain pericytes as a novel and myeloid-derived HIV reservoir

将大脑周细胞定义为一种新型的、源自骨髓的 HIV 储存库

基本信息

批准号：
10327440
负责人：
Michal Toborek
金额：
$ 48.36万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10327440
关键词：
AIDS/HIV problem Acute Address Astrocytes Attention Biology Blood - brain barrier anatomy Brain Cells Cerebrovascular Disorders Chronic Coupling DNA Data Dendritic Cells Development Endothelial Cells Functional disorder Future Gap Junctions Gene Expression Profile Goals Growth HIV HIV Infections HIV encephalitis HIV-1 Homeostasis Human Immune system Immunohistochemistry Impairment In Situ Hybridization In Vitro Individual Infection Inflammation Knowledge Latent virus infection phase Lead Life Cycle Stages Metabolic Methods Microglia Myelogenous Myeloid Cells Names National NeuroAids Tissue Consortium Neurocognitive Neurologic Pathogenesis Pathology Patients Pericytes Pharmacology Population Proviruses Publishing RNA Recording of previous events Reporter Research Role Sampling Signal Transduction Structure Viral Viral reservoir Virus Virus Replication Work base cell type cerebrovascular cohort comorbidity design experimental study functional outcomes high risk immune activation in situ imaging in vivo innovation latent infection macrophage monocyte nervous system disorder neuroAIDS neuropathology neurovascular neurovascular unit novel progenitor receptor sensor transcriptome transmission process

项目摘要

ABSTRACT HIV-1-infected individuals are at a higher risk for non-AIDS related co-morbidities, including cerebrovascular and neurological diseases. These pathologies may be driven, at least in part, by low levels of viral replication that persist in HIV-infected brains, which can lead to immune activation, chronic inflammation, and viral reactivation. Experiments on microglia, astrocytes, and brain pericytes indicate that these cells are all capable, to different degrees, to harbor HIV infection. We have pioneered research on HIV-1 infection in brain pericytes, and indicated that these cells possess the receptor profile enabling HIV-1 infection. Recent evidence on pericyte ontogeny identified that a substantial subpopulation of brain pericytes originates from myeloid progenitors. We recently demonstrated HIV-1-infected pericytes in human brains with HIV encephalitis. Furthermore, our new and exciting preliminary data suggest that brain pericytes may be capable of latent infection and reactivation, similar to other myeloid cells. Based on these observations, we hypothesize that brain pericytes are a key, albeit previously unrecognized, cell type for the formation of HIV-1 reservoirs in the CNS. The overarching goal of the current proposal is to characterize the latent HIV- 1 infection in brain pericytes as the necessary step for successful eradication of CNS reservoirs and HIV cure. Consistent with this goal, Specific Aims will evaluate the formation of latent HIV infection in brain pericytes both in vivo and in vitro. In a cohort of human brain samples with a history of achieved viral suppression obtained from the National NeuroAIDS Tissue Consortium (NNTC), we will determine whether brain pericytes harbor latent HIV-1 infections in HIV-suppressed patients (Aim 1). In addition, we will evaluate transcriptional signatures of latently HIV-1-infected human primary brain pericytes (Aim 2), and delineate functional outcomes associated with HIV infection of brain pericytes (Aim 3). The focus on the role of pericytes in the development of viral brain HIV reservoirs is an innovative and cutting- edge conceptual approach, consistent with the current RFA. Focusing on pericytes as a novel myeloid cell population in the context of HIV-1 infection and brain reservoirs has also a paradigm-changing potential and is likely to lead to new discoveries in the field. The planned experiments will help us to better characterize the pericyte reservoirs in the CNS in order to design future therapies for reservoir clearance and HIV cure.

抽象的 HIV-1感染的个体患非AID相关的合并症的风险较高，包括脑血管和神经疾病。这些病理可能至少部分通过低水平的病毒复制来驱动这持续存在于HIV感染的大脑中，这会导致免疫激活，慢性炎症和病毒重新激活。关于小胶质细胞，星形胶质细胞和脑周细胞的实验表明，这些细胞都有能力在不同的程度上，要蒙受艾滋病毒感染。我们对脑周细胞中的HIV-1感染进行了开创性的研究，并表明这些细胞具有使HIV-1感染的受体谱。最近的证据周细胞个体发育表明，大脑周细胞的大量亚群来自髓样祖先。我们最近证明了HIV脑炎的人大脑中受HIV-1感染的周细胞。此外，我们新的令人兴奋的初步数据表明，脑周细胞可能能够潜在感染和重新激活，类似于其他髓样细胞。基于这些观察，我们假设脑周细胞是一个关键，尽管以前未被认可，但用于形成HIV-1的细胞类型中枢神经系统中的水库。当前提案的总体目标是表征潜在的艾滋病毒 1在大脑周细胞中感染是成功根除中枢神经系统水库的必要步骤艾滋病毒治愈。与此目标一致，具体目标将评估大脑中潜在艾滋病毒感染的形成周细胞体内和体外。在具有已达到病毒史的人脑样本中从国家神经辅助组织（NNTC）获得的抑制脑周细胞含有hiv抑制患者的潜在HIV-1感染（AIM 1）。此外，我们将评估潜在的HIV-1感染的人类原发性脑周细胞的转录特征（AIM 2），并描绘与脑周细胞感染有关的功能结果（AIM 3）。关注周细胞在病毒脑HIV储层发展中的作用是一种创新和剪裁边缘概念方法，与当前的RFA一致。专注于周细胞作为一种新颖的髓样细胞 HIV-1感染和脑部储层的人口也具有改变范式的潜力，可能会导致该领域的新发现。计划的实验将帮助我们更好地描述中枢神经系统中的周围储层是为了设计未来的疗法，用于清除和艾滋病毒治疗。