Brain Myeloid Cells are Sources of HIV-associated Damage and Viral Dispersal

总结 艾滋病病毒在传播后很快就会感染大脑，但目前尚不清楚受感染的脑细胞如何导致艾滋病病毒 持久性以及这些细胞是否释放出可以在脑外接种细胞的活病毒。也不清楚 HIV持续存在如何导致局部细胞损伤，尽管炎症和外部因素（如抗逆转录病毒药物） [ARV]渗透和阿片类药物）可能会影响这种损害。这些新知识对艾滋病的治疗可能很重要 改善艾滋病毒感染者大脑健康的策略和方法。 本项目将解决RFA-MH-20-701的既定目标，髓样细胞在持久性中的作用， 从大脑中根除HIV-1储库，通过：（i）绘制HIV储库的大小，组成和活性， 脑骨髓细胞（BMC）与细胞密度和ARV和阿片类药物水平的关系，（ii）确定 BMC在HIV在中枢神经系统（CNS）内扩散和在ARV背景下穿过身体中的作用 治疗（ART）和治疗中断后，以及（iii）定义BMC中的HIV储存库大小和活性如何影响 与局部炎症和细胞损伤有关。 我们的目标是研究BMC在HIV持续存在、局部炎症诱导的损伤以及作为HIV感染源中的作用。 病毒可以从中枢神经系统扩散到周围器官。 该项目的基本原理得到了文献的支持，证明脑巨噬细胞和小胶质细胞可以 这些巨噬细胞和小胶质细胞的低周转率（从 几个月到几年）使它们成为艾滋病毒的独特储存库。虽然在静息T细胞中的艾滋病毒已经广泛地 尽管已经被表征，但是BMC作为停止ART后反弹的来源的作用还有待确定。此外，本发明还 BMC中的HIV可能会引发免疫反应，即使在ART期间，也会造成局部损伤。 我们的总体假设是，BMC（主要是小胶质细胞）有助于HIV在CNS中的持续存在， 区域异质性这些BMC中的HIV也可能导致炎症相关的脑损伤 并且在ART停止时有助于病毒传播。我们还假设艾滋病病毒的持续存在，局部损伤 和病毒扩散受局部抗逆转录病毒药物和阿片类药物水平的影响。 为了解决这些悬而未决的问题，我们的研究将收集和分析整个CNS的组织（白色和灰色 额叶皮质、丘脑、海马、基底神经节、小脑、脊髓）、回肠、脾脏、血液 和脑脊液（CSF）的利他性PWH登记在最后的礼物队列，正在进行的快速尸检研究。 一些参与者（n=15）将保持病毒抑制直至死亡，而另一些参与者（n=5）将希望 在死亡之前停止艺术。一半的人口将使用处方阿片类药物。 这些研究对威尔斯亲王医院十分重要，因为它们将为制定策略提供新的见解 以清除HIV感染并减轻炎症依赖性小胶质细胞诱导的神经损伤。

SUMMARY HIV infects the brain soon after transmission, but it is unknown how infected brain cells contribute to HIV persistence and whether these cells release viable virus that can seed cells outside the brain. It is also unclear how HIV persistence leads to local cellular damage, although inflammatory and external factors (like antiretroviral [ARV] penetration and opioids) likely impact such damage. Such new knowledge could be important for HIV cure strategies and ways to improve brain health in persons with HIV (PWH). This project will address stated objectives of RFA-MH-20-701, Role of Myeloid Cells in Persistence and Eradication of HIV-1 Reservoirs from the Brain, by: (i) mapping HIV reservoir size, composition, and activity in brain myeloid cells (BMC) in relation to cellular density and levels of ARV and opioids, (ii) determining the role of BMC in HIV dispersal within the central nervous system (CNS) and across the body in the setting of ARV treatment (ART) and after treatment interruption, and (iii) defining how HIV reservoir size and activity in BMC is associated with local inflammation and cell damage. Our goal is to examine the role of BMC in HIV persistence, local inflammatory-induced damage and as a source of viruses that can egress from the CNS to re-seed peripheral organs. The rationale for this project is supported by literature demonstrating that brain macrophages and microglia can harbor HIV that persists during modern ART. The low turnover of these macrophages and microglial cells (from months to years) make them unique reservoirs for HIV. While HIV in resting T cells has been extensively characterized, the role of BMC as a source of rebound upon cessation of ART is yet to be determined. Further, HIV in BMC likely triggers immune responses, even during ART, causing local damage. Our overall hypothesis is that BMC (primarily microglial cells) contribute to HIV persistence in the CNS with regional heterogeneity. HIV harbored in these BMC likely also causes inflammation-associated brain damage and contributes to viral dispersal when ART is stopped. We also hypothesize that HIV persistence, local damage and viral dispersal are influenced by local ARV and opioid levels. To address these open questions, our study will collect and analyze tissues throughout the CNS (white and grey matters of frontal cortex, thalamus, hippocampus, basal ganglia, cerebellum, spinal cord), ileum, spleen, blood and cerebrospinal fluid (CSF) of altruistic PWH enrolled in the Last Gift cohort, an ongoing rapid autopsy study. Some participants (n=15) will remain virally suppressed until the time of death, while others (n=5) will want to stop their ART before death. Half of the population will use prescription opioids. These studies will be important for PWH because they will provide new insights for the development of strategies to clear HIV infection and lessen inflammatory-dependent microglial-induced neurological damage.