Functional Cure of HIV Neurocognitive Disease by Induction of Innate Immunity

尽管对艾滋病毒感染者进行了抑制性抗逆转录病毒治疗，但仍维持其 免疫能力、脑功能障碍会发展并损害他们的生活质量。调查 HIV 在中枢神经系统 (CNS) 中的驻留、疾病和恢复我们研究了 EcoHIV 感染传统小鼠，这是一种嵌合 HIV，其趋向性从人类转变为 啮齿动物。受感染的小鼠确实会出现神经认知障碍（NCI）。我们发现与生俱来 Toll 样受体配体聚肌苷-聚胞苷酸 (poly I:C) 的免疫反应减少 病毒负担并恢复慢性感染 EcoHIV 的小鼠的认知功能。值得注意的是， Poly I:C 还可诱导长期反应，在很大程度上预防 EcoHIV 感染和 NCI。在这里， 我们将利用这些成功的治疗方法来实现小鼠中枢神经系统的功能性 EcoHIV 治愈 作为现有抗逆转录病毒疗法的补充。具体目标是 1) 利用逆转 通过对慢性感染小鼠进行间歇性 Poly I:C 治疗来识别 HIV NCI 基本抗病毒反应和关键抗病毒反应背后的基因表达变化 神经元基因恢复正常功能。特别令人感兴趣的是特定的识别 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 响应聚 I:C。 2) 研究通过长效poly I:C反应逆转HIV NCI 由慢性感染的小鼠。 Poly I:C 可诱导即时和长期的抗病毒程序 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 是利用基因组学和成像技术来揭示 HIV NCI 的途径以及 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 建立长期的多聚 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，包括长效多聚 I:C 反应，其中可能包括典型的干扰素 先天免疫训练计划。为了监测大脑中的 EcoHIV 感染和疾病，我们应 采用 QPCR 测量病毒负荷，采用径向臂水迷宫 (RAWM) 检测认知能力 缺陷、大脑 RNA-seq 揭示细胞基因失调、RNAscope 分配大脑感染 细胞类型，并通过共聚焦显微镜确定细胞类型安装保护先天 回应。由于先天免疫不是病原体特异性的，因此该探索性计划可能会揭示 诱导先天反应的方法，以防止其他病毒侵入大脑。

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.