CELL - AND CIRCUIT - SPECIFIC EXPLORATION OF HIV NEUROGENOMICS IN CONTEXT OF OPIATE AND COCAINE ABUSE

细胞和电路 - 阿片类药物和可卡因滥用背景下 HIV 神经基因组学的具体探索

• 批准号: 10728777
• 负责人: Schahram Akbarian
• 金额: $ 66.37万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728777
• 关键词: CELL; CIRCUIT; SPECIFIC; EXPLORATION; HIV

HIV-associated neurocognitive disorders (HAND) persist in the era of combination antiretroviral therapy (cART). Proof of HIV latency in human CNS is currently lacking, despite continued high prevalence of HIV- associated neurologic disease and increasing recognition of CNS viral escape in people stably suppressed with cART. One of the major issues regarding CNS HIV in need for study is HIV integration. With other words, whether CNS HIV integration has biologically significant impact, contributing to pathogenesis? Issues of CNS functional deficit are further complicated by the co-registered epidemic of opiate and other substance use disorders (SUD) in people living with HIV/AIDS (PLWHA), as SUD also have profound impact on CNS function, and potentially on HIV latency. Nowhere in the CNS is this more evident than in the neuroanatomic overlap of HIV and SUD in striatonigral dopaminergic circuitry and frontostriatal projections, sites of predilection for functional and neurobiologic disease as well as for increased burden of HIV infection. Accordingly, directly utilizing brain tissues in these regions, from neurologically well-characterized HIV-infected individuals with and without SUD, the goal of this application will be: (i) to replicate for brain some of the emerging genomic mechanisms recently discovered in peripheral cells, linking HIV host genome integration and virus latency to nuclear topography and open chromatin; (ii) to explore whether HIV signatures in transcriptomes and epigenomes in dopaminergic circuitry is associated with prospectively monitored neurological status in the years before death and exposure to drug of abuse; (iii) explore HIV expression and integration in potential reservoir cells of the brain, including microglia and astrocytes derived from HIV+ brain at autopsy and (iv) explore the impact of substance history on HIV integration and activity in primary microglial cultures derived from HIV- brains at autopsy and (vi) expose primary microglia in culture to drugs of abuse and HIV. The innovative experiments proposed here are expected to offer novel insights into epigenomic landscapes in specific brain cells and explore potential links between neurogenomic status of the infected brain and neurological and cognitive symptoms and substance abuse. While recognizing the high-risk aspects, these analyses will nevertheless have predictable, high gain benefits in understanding the complex neurobiology underlying HIV-associated CNS disease in PLWHA and SUD.

HIV相关神经认知障碍(HAND)坚持联合抗逆转录病毒治疗的时代 (购物车)。目前还缺乏人类中枢神经系统中艾滋病毒潜伏期的证据，尽管艾滋病毒的流行率仍然很高。 与神经系统疾病相关的疾病和对CNS病毒逃逸的认知度增加的稳定抑制的人 用购物车。关于需要研究的中枢神经系统艾滋病毒的主要问题之一是艾滋病毒的整合。换句话说， 中枢神经系统HIV整合是否在生物学上有重大影响，有助于发病机制？关于CNS的问题 功能缺陷因阿片剂和其他物质使用的共同登记流行而进一步复杂化 艾滋病毒/艾滋病(PLWHA)患者的疾病(SUD)，因为SUD也对中枢神经系统功能有深远影响， 以及潜在的艾滋病毒潜伏期。这一点在中枢神经系统的神经解剖学重叠中最为明显。 HIV和SUD在纹状体黑质多巴胺能回路和额纹状体投射中的分布 这与功能性和神经生物学疾病以及艾滋病毒感染负担加重有关。因此，直接 利用这些区域的脑组织，来自神经学特征良好的艾滋病毒感染者， 在没有SUD的情况下，这项应用的目标将是：(I)为大脑复制一些新兴的基因组 最近在外周细胞中发现的机制，将艾滋病毒宿主基因组整合和病毒潜伏时间联系起来 核形态和开放染色质；(2)探索转录本和染色质中的艾滋病毒签名 多巴胺能回路中的表观基因组与前瞻性监测的神经状态有关 死亡和接触滥用药物的前几年；(3)探讨艾滋病毒的表达和潜在整合 尸检中来自HIV阳性脑的储藏细胞，包括小胶质细胞和星形胶质细胞以及(Iv) 探讨物质史对小胶质细胞原代培养中HIV整合和活性的影响 (Vi)使原代培养的小胶质细胞暴露于滥用药物和艾滋病毒的药物中。这个 这里提出的创新实验有望为表观基因组学景观提供新的见解 并探索受感染大脑的神经基因组状态与 神经和认知症状以及药物滥用。在认识到高风险方面的同时，这些 然而，分析将在理解复杂的神经生物学方面具有可预见的、高收益的好处。 PLWHA和SUD中潜在的艾滋病毒相关中枢神经系统疾病。