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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.

摘要