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

• 批准号: 10432128
• 负责人: Michal Toborek
• 金额: $ 47.14万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10432128
• 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; 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

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.

摘要 HIV-1感染者患非艾滋病相关合并症的风险更高，包括脑血管疾病 和神经系统疾病。这些病理可能至少部分地由低水平的病毒复制驱动 这些蛋白质在HIV感染的大脑中持续存在，这可能导致免疫激活、慢性炎症和病毒感染。 重新激活对小胶质细胞、星形胶质细胞和脑周细胞的实验表明，这些细胞都有能力， 在不同程度上，携带艾滋病毒感染。我们率先研究了大脑周细胞中的HIV-1感染， 并表明这些细胞具有使HIV-1感染成为可能的受体谱。最近的证据表明， 周细胞个体发育鉴定了脑周细胞的大量亚群起源于髓样细胞， 祖先我们最近证明了HIV-1感染的周细胞在人类大脑与HIV脑炎。 此外，我们新的和令人兴奋的初步数据表明，脑周细胞可能能够潜伏 感染和再活化，类似于其他骨髓细胞。基于这些观察，我们假设， 脑周细胞是HIV-1形成的一种关键细胞类型，尽管以前未被认识到 中枢神经系统中的储库。目前提案的首要目标是描述潜伏的艾滋病毒- 1例脑周细胞感染是成功根除CNS储库的必要步骤， 艾滋病治疗。与这一目标相一致，特异性目的将评估大脑中潜伏性艾滋病毒感染的形成 在体内和体外的周细胞。在一组有病毒感染史的人脑样本中， 从国家神经艾滋病组织联盟（NNTC）获得的抑制，我们将确定是否 脑周细胞在HIV抑制患者中潜伏HIV-1感染（Aim 1）。此外，我们将评估 潜伏性HIV-1感染的人原代脑周细胞的转录特征（Aim 2），并描绘 脑周细胞的HIV感染相关的功能结果（目的3）。 对周细胞在病毒脑HIV储库发展中的作用的关注是一个创新和切割- 边缘概念方法，与当前RFA一致。关注周细胞作为一种新的髓样细胞 在HIV-1感染和脑储库的背景下，人口也具有改变范式的潜力， 很可能会在这一领域带来新的发现。计划中的实验将有助于我们更好地描述 为了设计用于储库清除和HIV治愈的未来疗法，