Misfolded Protein Aggregates in HIV infection

摘要 大量艾滋病毒感染者发展为痴呆症和认知功能障碍， HIV相关的神经认知障碍（HAND）。的分子机制 负责手还没有很好地理解，但证据表明，许多相似之处， 阿尔茨海默病（AD）和相关的神经退行性疾病（ND）。事实上， 已经表明HIV感染者发展出AD的神经病理学特征， 包括β淀粉样蛋白（Aβ）斑块的沉积和神经纤维缠结， 磷酸化-Tau（pTau）。然而，目前还不清楚这些异常是否与 特别是与艾滋病毒感染和发挥作用的神经系统异常观察到的患者 手的影响。一个主要的问题，以了解分子机制牵连在 艾滋病病毒感染对脑变性的影响是缺乏合适的模型来研究的影响， 人类大脑中的HIV以及与ND相关的病理过程的相互作用。主要 该项目的目标是全面研究在细胞中错误折叠的蛋白质聚集体的存在。 大脑和艾滋病毒感染者的生物液体，有或没有手，也与 联合抗逆转录病毒治疗（cART）。我们的假设是艾滋病病毒 感染或用cART治疗会引发促进错误折叠和早期凋亡的事件。 易于在ND中聚集的蛋白质的寡聚化和/或减少清除途径 通常会消除这些异常折叠的蛋白质。为了验证这一假设，我们提出了 以下具体目的：（1）检测和表征蛋白质中错误折叠的蛋白质聚集体， HIV感染者的大脑。(2)检测人的生物体液中错误折叠的蛋白质聚集体 HIV感染者尝试开发一种生化检测方法来帮助HAND诊断， 监测其进展。(3)一种新的研究HIV感染效应的体外模型的建立 用实验室制造的类脑脑器官来改变大脑。 本研究的结果可能有助于揭示错误折叠的细胞在细胞内的作用。 蛋白质聚集体在HIV感染引起的神经系统异常中的作用， AD和相关ND与HAND发病机制之间的潜在相互作用。这个项目可能 为HAND的生化诊断提供了新的方法和模型 研究HIV感染对CNS的影响。

ABSTRACT A large number of people living with HIV develop dementia and cognitive dysfunction often referred as HIV-associated neurocognitive disorder (HAND). The molecular and cellular mechanisms responsible for HAND are not well understood, but evidence suggests many similarities with Alzheimer's disease (AD) and related neurodegenerative disorders (NDs). Indeed, various reports have shown that HIV-infected people develop neuropathological features characteristic of AD, including deposition of amyloid-beta (Aβ) plaques and neurofibrillary tangles composed by phosphorylated-Tau (pTau). However, it is unclear whether these abnormalities are associated specifically with HIV infection and play a role in the neurological abnormalities observed in patients affected by HAND. A major problem to understand the molecular mechanisms implicated in the impact of HIV infection in brain degeneration is the lack of appropriate models to study the effect of HIV in the human brain and the interaction with pathological processes implicated in NDs. The major goal of this project is to comprehensively study the presence of misfolded protein aggregates in the brain and biological fluids of HIV-infected people, with or without HAND and also in relationship to treatment with combination antiretroviral therapy (cART). Our working hypothesis is that HIV infection or treatment with cART initiates events that promote the misfolding and early oligomerization of the proteins prone to aggregate in NDs and/or reduces the clearance pathways that normally eliminate these abnormally folded proteins. To test this hypothesis, we propose the following specific aims: (1) Detection and characterization of misfolded protein aggregates in the brain of HIV-infected patients. (2) Detection of misfolded protein aggregates in biological fluids of HIV-infected patients to attempt development of a biochemical assay to help HAND diagnosis and monitor its progression. (3) Development of a novel in vitro model to study the effect of HIV infection in brain alterations using lab-generated brain-like cerebral organoids. The findings generated in this project may contribute to enlighten the putative role of misfolded protein aggregates in the neurological abnormalities induced by HIV infection and understand the potential interaction between AD and related NDs with the pathogenesis of HAND. This project may also contribute to develop a novel method for biochemical diagnosis of HAND, and relevant model systems to study the CNS effect of HIV infection.