Functional Cure of HIV Neurocognitive Disease by Induction of Innate Immunity

通过诱导先天免疫对 HIV 神经认知疾病进行功能性治愈

基本信息

批准号：
10671714
负责人：
MARY Jane POTASH
金额：
$ 21.13万
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：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671714
关键词：
Animals Antiviral Response Bacterial Infections Brain Cells Central Nervous System Chronic Cognition Disorders Cognitive deficits Complement Confocal Microscopy Development Disease Elements Exposure to Gene Expression Genes Genomics Goals HIV HIV Infections HIV-associated neurocognitive disorder Human Imaging Techniques Immune Immune response Immunity Immunocompetence Immunocompetent Impaired cognition Impairment Infection Innate Immune Response Interferon Type I Invaded Ligands Macrophage Maintenance Measures Mediating Microglia Monitor Mus Natural Immunity Neurocognitive Neurocognitive Deficit Neuronal Dysfunction Neurons Poly C Poly I-C Quality of life Radial Recovery Rodent Route Stimulus System Techniques Testing Toll-like receptors Training Training Programs Tropism Viral Virus Virus Diseases antiretroviral therapy arm brain cell brain dysfunction cell type cognitive function design exposure route functional restoration fungus interest novel strategies pathogen prevent programs residence response transcriptome sequencing water maze

项目摘要

Despite suppressive antiretroviral therapy in HIV infected human beings that maintains their immunocompetence, brain dysfunction develops and impairs their quality of life. To investigate HIV residence, disease, and recovery in the central nervous system (CNS) we have studied the infection of conventional mice by EcoHIV, a chimeric HIV with tropism switched from human to rodent. Infected mice reliably develop neurocognitive impairment (NCI). We found that innate immune responses to Toll-like receptor ligand polyinosinic-polycytidylic acid (poly I:C) reduce virus burden and restore cognitive function in mice chronically infected by EcoHIV. Remarkably, poly I:C also induces a long-lived response that largely prevents EcoHIV infection and NCI. Here, we shall exploit these successful treatments to achieve functional EcoHIV cure in the murine CNS as a complement to existing antiretroviral therapies. The Specific Aims are 1) to exploit reversal of HIV NCI through intermittent poly I:C treatment of chronically infected mice to identify the changes in gene expression underlying both the essential antiviral responses and the critical neuronal genes restored to normal function. Of particular interest is the identification of specific cell types mediating protective immunity and their specific products, since all brain cell types can respond to poly I:C. 2) to investigate reversal of HIV NCI through long-lived poly I:C responses by chronically infected mice. Poly I:C induces both immediate and long-lived antiviral programs that prevent EcoHIV infection and the development of HIV NCI. Our overall goal in this application is to bring genomics and imaging techniques to expose the routes of HIV NCI as well as the antiviral routes that restore function. Here, we will test whether chronically infected mice can mount a long-lived poly I:C response that restores normal cognitive function. It will be critical to compare the gene expression programs initiated by intermittent poly I:C treatment, likely Type I interferon, to those comprising the long-lived poly I:C response that may include the canonical innate immune training program. To monitor EcoHIV infection and disease in the brain we shall employ QPCR to measure virus burden and radial arm water maze (RAWM) to detect cognitive defects, brain RNA-seq to reveal cellular gene dysregulation, RNAscope to assign brain infection to cell types, and confocal microscopy to determine cell types mounting protective innate responses. Since innate immunity is not pathogen specific, this exploratory program may reveal approaches to induce innate responses that protect against other viruses invading the brain.

尽管抑制了艾滋病毒感染的抗逆转录病毒疗法，但仍保持免疫能力，大脑功能障碍会发展并损害其生活质量。调查中枢神经系统（CNS）中的HIV居住，疾病和康复 Ecohiv感染常规小鼠，一种嵌合艾滋病毒，与人类的嵌合HIV从人类转变为啮齿动物。感染的小鼠可靠地发展出神经认知障碍（NCI）。我们发现那个天生对Toll样受体配体聚激素聚胞酸酸（Poly I：C）的免疫反应降低病毒负担和恢复由EcoHIV长期感染的小鼠的认知功能。值得注意的是 Poly I：C还引起了长期的反应，从而在很大程度上阻止了生态感染和NCI。这里，我们将利用这些成功的治疗方法来实现鼠CNS中的功能性生态治疗作为现有抗逆转录病毒疗法的补充。具体目标是1）利用逆转 HIV NCI通过间歇性Poly I：C治疗长期感染小鼠的治疗基因表达的变化是基本抗病毒反应和关键的基因表达的变化神经元基因恢复到正常功能。特别感兴趣的是特定的识别细胞类型介导保护性免疫及其特定产品，因为所有脑细胞类型都可以回应Poly I：c。 2）通过长寿命poly I：C响应研究HIV NCI的逆转由长期感染的小鼠。 Poly I：C诱导立即和长寿命的抗病毒程序这可以防止生态感染和HIV NCI的发展。我们在此应用程序中的总体目标是带来基因组学和成像技术，以揭示HIV NCI的路线以及恢复功能的抗病毒路线。在这里，我们将测试长期感染的小鼠是否可以安装长寿命的Poly I：C响应，该响应恢复正常的认知功能。这将是至关重要的比较通过间歇性poly I：C处理启动的基因表达程序，可能是I型干扰素，包括构成可能包括规范的长期poly I：C响应的人先天免疫训练计划。为了监测大脑的生态感染和疾病，我们将使用QPCR测量病毒负担和径向臂水迷宫（RAWM）来检测认知缺陷，脑RNA-seq以揭示细胞基因失调，rnascope以分配脑感染细胞类型和共聚焦显微镜确定细胞类型安装保护性先天回答。由于先天免疫不是病原体的特定于病原体，因此该探索性程序可能会揭示诱导先天反应的方法，以防止入侵大脑的其他病毒。