Single nuclei transcriptome profiling in addiction circuitry of the HIV+ brain

HIV相关神经认知障碍(HAND)坚持联合抗逆转录病毒时代 治疗(购物车)。HIV潜伏期和HIV转录本在人中枢神经系统中的细胞特异性表达 不完全了解，尽管艾滋病毒相关神经疾病的发病率仍然很高， 使用CART稳定抑制的患者对中枢神经系统病毒逃逸的认知度增加。其中一个主要的 需要研究的有关中枢神经系统艾滋病毒的问题是艾滋病毒的整合。换句话说，无论是中枢神经系统艾滋病毒 整合对生物学有重大影响，对发病机制有贡献吗？关于CNS功能的问题 阿片剂和其他物质使用的共同登记流行病使赤字进一步复杂化 艾滋病毒/艾滋病患者的疾病(PLWHA)，因为SUD对中枢神经系统也有深远的影响 功能，并可能对艾滋病毒的潜伏期。在中南半球，这一点最为明显。 HIV和SUD在纹状体黑质多巴胺能环路和额纹状体的神经解剖重叠 投射，功能性和神经生物学疾病的好发部位，以及增加的负担 艾滋病毒感染的可能性。因此，直接利用这些区域的脑组织，从神经学上来说- 这个应用程序的目标是：(I) 为大脑复制最近在外周细胞中发现的一些新兴的基因组机制， 将艾滋病毒宿主基因组整合和病毒潜伏期与核形态和开放染色质联系起来； 探索转录本和表观基因组中的HIV信号是否存在于多巴胺能回路中 包括额叶和纹状体靶点与前瞻性监测的神经学相关 死亡前几年的状况和接触滥用药物的情况；(3)探讨艾滋病毒的潜在表现 大脑的储藏细胞，包括小胶质细胞。这里提出的创新实验是令人期待的 提供对特定脑细胞转录情况的新见解，并探索潜在的联系 感染脑的神经基因组状态与神经和认知症状之间的关系 滥用药物。虽然认识到高风险方面，但这些分析仍将 在理解艾滋病毒背后的复杂神经生物学方面，可预测的、高收益的好处- PLWHA和SUD相关的中枢神经系统疾病。

HIV-associated neurocognitive disorders (HAND) persist in the era of combination antiretroviral therapy (cART). HIV latency, and cell-specific expression of HIV transcript in human CNS remains incompletely understood, 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 including frontal and striatal targets is associated with prospectively monitored neurological status in the years before death and exposure to drug of abuse; (iii) explore HIV expression in potential reservoir cells of the brain, including microglia. The innovative experiments proposed here are expected to offer novel insights into transcriptomic 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.