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：
9153356
负责人：
MARY Jane POTASH
金额：
$ 71.67万
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/9153356
关键词：
Animal Model Antiviral Agents Antiviral Response Attenuated Basal Ganglia Bioinformatics Biological Assay Brain Brain Diseases Brain region Cells Clinical Code DNA Development Elements Family Fluorescence Microscopy Gene Expression Genes HIV HIV Infections HIV-associated neurocognitive disorder Hippocampus (Brain)Human Immune Immune response Impaired cognition Individual Infection Inflammatory 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 Methods MicroRNAs Microscopy Monitor Mus Natural Immunity Neurocognitive Deficit Neuropathogenesis Pathogenesis Patients Peripheral Prevention Proteins RNA Resistance Resources Role Route SIV Sampling Staging System Systemic infection TLR2 gene Technology Testing Time Toll-like receptors Transcript Untranslated RNA Viral reservoir Virus Work antiretroviral therapy base behavior test brain tissue cell type conditioned fear cytokine digital disorder control frontal lobe gene product immune function in vivo learned behavior macrophage monocyte nano-string novel strategies novel therapeutics prevent protein biomarkers public health relevance receptor response therapy design transmission process 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（由应用提供）：HIV感染中的抗逆转录病毒疗法可保留免疫功能，但允许在约50％的治疗患者中发展神经认知障碍（NCI）。我们提出了一条新途径，以预防或治疗与HIV相关的NCI。该应用旨在检验以下假设：单核细胞中先天抗病毒反应的诱导可以减轻大脑中的HIV感染两个层面：通过防止建立HIV储量并通过中断神经病性基因的表达，导致NCI。单核细胞是大脑中HIV的主要靶标。他们的艾滋病毒中位数进入大脑，但可以安装阻断艾滋病毒感染的先天免疫反应。体内I型干扰素反应减少了感染了嵌合HIV的小鼠的神经病发生；它们限制了人类和ECOHIV感染小鼠的HIV传播，并可以控制猕猴中的SIV感染。我们建议使用传统和各种敲除小鼠的生态感染及其诱导NCI，以定义巨噬细胞对巨噬细胞对艾滋病毒的保护的基础，以防止大脑或其相关脑部疾病中的HIV感染。具体目的是：1）单独测试配体向类似收费的受体（TLR）2、3、7/8和9，并结合预防Ecohiv转移到大脑的结合； 2）测试TLR配体进行沉默 NCI的大脑和逆转的HIV水库； 3）定义宿主的关键抗病毒决定器 TLR配体在动物模型中预防或治疗手动治疗期间的反应，通过使用基因表达平台，多重技术，生物信息学和荧光显微镜分析编码和调节RNA和蛋白质。 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预防或控制NCI的生态感染。如果成功，这些研究将描述新的方法和药物，以进一步临床发育，以治疗受HIV感染的人中的NCI并保留大脑功能。