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 感染者患非艾滋病相关并发症（包括脑血管疾病）的风险较高和神经系统疾病。这些病理学可能至少部分是由低水平的病毒复制引起的持续存在于感染艾滋病毒的大脑中，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、星形胶质细胞和大脑周细胞的实验表明，这些细胞都有能力，不同程度地存在HIV感染。我们开创了关于大脑周细胞中 HIV-1 感染的研究，并表明这些细胞具有能够感染 HIV-1 的受体特征。最近的证据周细胞个体发育发现大脑周细胞的大量亚群起源于骨髓祖先。我们最近证明了患有 HIV 脑炎的人类大脑中存在 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，大脑周细胞可能具有潜在的感染和重新激活，与其他骨髓细胞类似。根据这些观察，我们假设大脑周细胞是形成 HIV-1 的关键细胞类型，尽管之前未被认识到中枢神经系统中的水库。当前提案的总体目标是描述潜在的 HIV- 1 脑周细胞感染是成功根除中枢神经系统储存库的必要步骤艾滋病毒治愈。与这一目标一致，Specific Aims 将评估大脑中潜在 HIV 感染的形成体内和体外的周细胞。在一组具有病毒感染历史的人类大脑样本中从国家神经艾滋病组织联盟 (NNTC) 获得抑制，我们将确定是否 HIV 抑制患者的大脑周细胞隐藏着潜在的 HIV-1 感染（目标 1）。此外，我们还将评估潜在感染 HIV-1 的人类原代脑周细胞的转录特征（目标 2），并描绘与大脑周细胞 HIV 感染相关的功能结果（目标 3）。对周细胞在病毒脑部 HIV 储存库发育中的作用的关注是一项创新和前沿的研究。边缘概念方法，与当前的 RFA 一致。关注周细胞作为一种新型骨髓细胞 HIV-1 感染和脑储存库背景下的人群也具有改变范式的潜力很可能会在该领域带来新的发现。计划中的实验将帮助我们更好地表征中枢神经系统中的周细胞储库，以设计未来的储库清除和艾滋病毒治疗疗法。