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

艾滋病毒相关的神经认知障碍（HAND）在联合抗逆转录病毒时代仍然存在 治疗（cART）HIV潜伏期和HIV转录物在人CNS中的细胞特异性表达仍然存在 尽管艾滋病毒相关神经系统疾病的患病率仍然很高， 增加对cART稳定抑制人群中CNS病毒逃逸的认识。CNS问题 阿片剂和其他药物使用的共同登记流行使功能缺陷进一步复杂化 艾滋病毒/艾滋病（PLWHA）感染者的疾病（SUD），因为SUD对CNS也有深远的影响。 功能，并可能对艾滋病毒潜伏期。在中枢神经系统中，这一点比神经解剖学更明显。 HIV和SUD在纹状体黑质多巴胺能回路及其皮质投射区的重叠， 前扣带皮层，功能性和神经生物学疾病以及 增加了艾滋病毒感染的负担。因此，直接利用这些区域的脑组织， 本申请的目的是在神经学上充分表征患有和不患有SUD的HIV感染个体 将探讨多巴胺能神经回路转录组中的HIV信号是否在 c i n g u l a t e t a r g e t s与前几年前瞻性监测的神经系统状态相关 死亡和暴露于滥用药物;（iii）探索HIV在大脑潜在储库细胞中的表达， 包括小胶质细胞。本文提出的创新实验有望为以下方面提供新的见解： 特定脑细胞中的转录组景观，并探索神经基因组状态之间的潜在联系 感染的大脑和神经和认知症状以及药物滥用。同时认识 尽管存在高风险方面，但这些分析仍将在以下方面具有可预测的高增益收益： 了解PLWHA和SUD中HIV相关CNS疾病的复杂神经生物学基础。

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. 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 its cortical projection areas including the anterior cingulate cortex, 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 to explore whether HIV signatures in transcriptomes in dopaminergic circuitry i n c l u d i n g c i n g u l a t e t a r g e t s 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.