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

• 批准号: 10548392
• 负责人: MARY Jane POTASH
• 金额: $ 25.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10548392
• 关键词: Animals; Antiviral Response; Bacterial Infections; Brain; Cells; Chronic; Cognition Disorders; Cognitive deficits; Complement; Confocal Microscopy; Development; Disease; Elements; Exposure to; Gene Expression; Genes; Genomics; Goals; HIV; HIV Infections; Human; Imaging Techniques; Immune; Immune response; Immunity; Immunocompetence; Immunocompetent; Impaired cognition; Impairment; Infection; Innate Immune Response; Interferon Type I; Invaded; Ligands; Maintenance; Measures; Mediating; Microglia; Monitor; Mus; Natural Immunity; Neuraxis; 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; Virus; Virus Diseases; antiretroviral therapy; arm; brain cell; brain dysfunction; cell type; cognitive function; design; exposure route; functional restoration; fungus; interest; macrophage; novel strategies; pathogen; prevent; programs; residence; response; transcriptome sequencing; water maze

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.

尽管抑制性抗逆转录病毒疗法在HIV感染者中维持了其 免疫功能低下，脑功能障碍发展并损害他们的生活质量。探讨 HIV在中枢神经系统（CNS）中的驻留、疾病和恢复，我们研究了 EcoHIV感染常规小鼠，EcoHIV是一种嵌合HIV，其嗜性从人转变为 啮齿动物。感染的小鼠可靠地发展神经认知障碍（NCI）。我们发现， 对Toll样受体配体聚肌苷酸-聚胞苷酸（poly I：C）降低免疫应答 病毒负荷和恢复认知功能的小鼠慢性感染EcoHIV。值得注意的是， poly I：C还诱导长期反应，其在很大程度上防止EcoHIV感染和NCI。在这里， 我们将利用这些成功的治疗方法在小鼠中枢神经系统中实现功能性EcoHIV治愈 作为现有抗逆转录病毒疗法的补充。具体目标是：1）利用反转 通过对慢性感染小鼠进行间歇性poly I：C治疗， 基因表达的变化是基本的抗病毒反应和关键的 神经元基因恢复正常功能。特别令人感兴趣的是， 介导保护性免疫的细胞类型及其特定产物，因为所有脑细胞类型都可以 对多聚腺苷酸有反应。2)研究HIV NCI通过长寿命poly I：C应答的逆转 被慢性感染的老鼠。Poly I：C诱导即时和长期抗病毒程序 预防EcoHIV感染和HIV NCI的发展。我们在此应用程序中的总体目标 是将基因组学和成像技术用于揭示HIV NCI的传播途径， 恢复功能的抗病毒途径。在这里，我们将测试慢性感染的小鼠是否可以 产生长寿命的聚I：C反应，恢复正常的认知功能。这将是至关重要的， 比较间歇性poly I：C治疗启动的基因表达程序，可能是I型 干扰素，到那些包含长寿命的多聚I：C应答的干扰素，所述长寿命的多聚I：C应答可以包括典型的 先天免疫训练计划为了监测大脑中的EcoHIV感染和疾病，我们将 采用QPCR测量病毒负荷和放射臂水迷宫（RAWM）检测认知功能 缺陷，大脑RNA-seq揭示细胞基因失调，RNAscope分配大脑感染 共聚焦显微镜，以确定细胞类型安装保护性先天 应答由于先天免疫不是病原体特异性的，这个探索性的项目可能会揭示 诱导先天反应的方法，以防止其他病毒入侵大脑。