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Toward control of HIV neuropathogenesis by innate immunity

通过先天免疫控制 HIV 神经发病机制

基本信息

批准号：
9232229
负责人：
MARY Jane POTASH
金额：
$ 70.66万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9232229
关键词：
Animal Model Antiviral Agents Antiviral Response Attenuated Basal Ganglia Behavior Bioinformatics Biological Assay Brain Brain Diseases Brain region Cells Chronic Code DNA Development Elements Family Fluorescence Microscopy Gene Expression Genes HIV HIV Infections HIV therapy HIV-associated neurocognitive disorder Hippocampus (Brain)Human Immune Immune response Impaired cognition Individual Infection Inflammatory Innate Immune Response Interferon Type I Interferons Interruption Intranasal Administration Investigation Kinetics Knock-out Knockout Mice Learning Life Cycle Stages Ligands Macaca Measurement Mediating Mediator of activation protein Memory Memory impairment Methods MicroRNAs Microscopy Monitor Mus Natural Immunity Neurocognitive Deficit Neuropathogenesis Pathogenesis Patients Peripheral Prevention Proteins RNA Resistance Resources Role Route SIV Sampling System Systemic infection TLR2 gene Technology Testing Time Toll-like receptors Transcript Untranslated RNA Viral reservoir Virus Work antiretroviral therapy behavior test brain tissue cell type clinical development conditioned fear cytokine digital disorder control frontal lobe gene product immune function in vivo macrophage monocyte nano-string novel strategies novel therapeutics prevent protein biomarkers public health relevance response therapy design transmission process type I interferon receptor viral DNA

项目摘要

DESCRIPTION (provided by applicant): Antiretroviral therapy in HIV infection preserves immune function but allows development of neurocognitive impairment (NCI) in about 50% of treated patients. We propose a new route to prevent or treat HIV-associated NCI. This application aims to test the hypothesis that induction of innate antiviral responses in monocytes can mitigate HIV infection in the brain at two levels: by preventing establishment of the HIV reservoir and by interruption of expression of neuropathogenic gene products leading to NCI. Monocytic cells are the primary target of HIV in the brain; they mediate HIV entry into the brain, but they can mount innate immune responses that block HIV infection. In vivo Type I interferon responses reduce neuropathogenesis in mice infected by chimeric HIV, EcoHIV; they restrict HIV transmission in human beings and in EcoHIV infected mice and can control SIV infection in macaques. We propose to use EcoHIV infection of conventional and various knockout mice and its induction of NCI, to define the basis of protective innate immune responses of macrophages to HIV in mice to prevent HIV infection in the brain or its associated brain disease. The Specific Aims are: 1) to test ligands to Toll-like receptors (TLR) 2, 3, 7/8, and 9 singly and in combinations for prevention of EcoHIV transit to the brain; 2) to test TLR ligands for silencing of the HIV reservoir in the brain and reversal of NCI; 3) to define key antiviral determinants of host responses during prevention or therapy of HAND by TLR ligands in an animal model by analysis of coding and regulatory RNAs and proteins using gene expression platforms, multiplex technology, bioinformatics, and fluorescence microscopy in specific cell types. Methods will include intranasal administration of TLR ligands, digital droplet PCR for sensitive measurement of viral DNA, fear conditioning assays of behavior and learning, assay of antiviral proteins in macrophages and brain by multiplex assays and microscopy, and assays of both coding and microRNA expression by NanoString technology and identification of antiviral genes or miRNA common to responses to multiple TLR ligands that prevent or control EcoHIV infection of NCI. If successful, these studies will describe novel approaches and agents for further clinical development to treat NCI in HIV infected people and to preserve brain function.

描述（由申请人提供）：HIV 感染的抗逆转录病毒治疗可保留免疫功能，但约 50% 的治疗患者会出现神经认知障碍 (NCI)。我们提出了一种预防或治疗 HIV 相关 NCI 的新途径。本申请旨在测试这样的假设：诱导单核细胞先天抗病毒反应可以在两个层面上减轻大脑中的 HIV 感染：防止 HIV 储存库的建立以及中断导致 NCI 的神经病原基因产物的表达。单核细胞是大脑中艾滋病毒的主要目标；它们介导艾滋病毒进入大脑，但它们可以引发先天免疫反应，阻止艾滋病毒感染。体内 I 型干扰素反应可减少嵌合 HIV、EcoHIV 感染小鼠的神经发病机制；它们限制 HIV 在人类和 EcoHIV 感染小鼠中的传播，并可以控制猕猴中的 SIV 感染。我们建议利用常规和各种基因敲除小鼠的 EcoHIV 感染及其诱导的 NCI，来确定小鼠巨噬细胞对 HIV 的保护性先天免疫反应的基础，以预防大脑中的 HIV 感染或其相关的脑部疾病。具体目标是： 1) 单独或组合测试 Toll 样受体 (TLR) 2、3、7/8 和 9 的配体，以预防 EcoHIV 转运至大脑； 2) 测试 TLR 配体的沉默大脑中的 HIV 储存库和 NCI 的逆转； 3）定义宿主的关键抗病毒决定因素通过使用基因表达平台、多重技术、生物信息学和特定细胞类型的荧光显微镜分析编码和调节RNA和蛋白质，在动物模型中通过TLR配体预防或治疗HAND期间的反应。方法包括鼻内施用 TLR 配体、用于灵敏测量病毒 DNA 的数字微滴 PCR、行为和学习的恐惧调节测定、通过多重测定和显微镜测定巨噬细胞和大脑中的抗病毒蛋白、通过 NanoString 技术测定编码和 microRNA 表达，以及识别对多种 TLR 配体反应常见的抗病毒基因或 miRNA，预防或控制 NCI 的 EcoHIV 感染。如果成功，这些研究将描述用于进一步临床开发的新方法和药物，以治疗 HIV 感染者的 NCI 并保留大脑功能。