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Targeting latent HIV Astroglial Reservoirs without Reactivation

靶向潜在的 HIV 星形胶质细胞库而不重新激活

基本信息

批准号：
9350661
负责人：
Anuja Ghorpade
金额：
$ 21.9万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9350661
关键词：
Address Astrocytes Biological Markers Biological Models Blood - brain barrier anatomy Brain Cell Line Cells Chronic Color Comorbidity Cytomegalovirus DNA Data Disease Excision Failure Fluorescent Dyes Future Gene Expression Genes Goals Guide RNA HIV HIV Infections HIV Seropositivity HIV therapy HIV-1 HIV-associated neurocognitive disorder Homeostasis Human Individual Infection Inflammation Investigation Ligands Mediating Modeling Monitor Nerve Degeneration Neuroglia Neurologic Neurons Patients Peripheral Blood Mononuclear Cell Physiological Population Proviruses Recovery Reporter Research Personnel Sorting - Cell Movement System TNF gene Techniques Therapeutic Time Tissues Vesicular stomatitis Indiana virus Viral Viral Genes Viral Proteins Viral reservoir Virion Virus Virus Diseases Virus Latency Work antiretroviral therapy astrogliosis base cytokine digital extracellular improved insight latent infection nanoparticle neuroAIDS neuroinflammation novel novel therapeutics prevent promoter receptor response restoration scale up synaptic function targeted biomarker therapeutic gene tool

项目摘要

Project Summary/Abstract Despite the advent of successful antiretroviral therapy (ART), the quest for a human immunodeficiency virus (HIV)-1 cure continues. In order to achieve total eradication, we must successfully resolve persistent viral reservoirs in various tissue compartments. HIV-associated neurocognitive disorders (HAND) remain a significant societal burden in post-ART era. In response to the RFA-MH-17-100, we propose to uncover strategies to address astrocytes as a major CNS reservoir for HIV-1. Our preliminary data show HIV-1 latency can be recapitulated in cultured human astrocytes. The lack of powerful experimental tools to evaluate latency versus reactivation has in part, been responsible for the lack of information in viral latency in the CNS. We propose to employ the powerful dual color HIV-1 reporter virus that harbors CMV-driven mCherry (red, R) and HIV-1 LTR-driven GFP (green, G). Preliminary studies using primary human astrocytes infected with RG-HIV-1 VSV-pseudotyped virions are shown. All astrocytes infected with RG- HIV-1 express the CMV-driven mCherry (red), whereas only those that have an active HIV-1 LTR will express GFP (green) and are positive for HIV-1 p24. Red-alone astrocytes (mCherry+/GFP-) represent latently infected cells amenable to easy monitoring, sorting, manipulation and mechanistic investigations. We have established this model system using primary human astrocytes, which presents a simple, convenient and powerful tool for these works. We propose that latently infected astrocytes express identifiable biomarkers, even in the absence of reactivation. And that guide RNA/Cas9 editing can excise or silence proviral gene expression to prevent reactivation and improve astrocyte physiological function. To mitigate the conundrum of distinguishing latently infected astrocytes from those that have active HIV-1 LTR function, our first goal is to identify targetable biomarkers for HIV-1 latency in human astrocytes (Aim 1). Second, we will target latently infected astrocytes without reactivation using guide RNA and Cas9 gene editing techniques to excise proviral components, rendering it silent and incapable of reactivation (Aim 2). A successful integration of Aims 1 and 2 will lead to novel therapies to cure and eradicate HIV-1 CNS reservoirs. In summary, these investigations responding to RFA-MH-17-100 will provide novel and timely insight into delineating approaches to identify and target astrocyte viral reservoirs, key CNS barriers to HIV-1/HAND cure, and eliminate them without viral reactivation.

项目总结/文摘