Misfolded Protein Aggregates in HIV infection

摘要 大量艾滋病毒携带者患上痴呆症和认知功能障碍 作为艾滋病毒相关的神经认知障碍(手)。分子和细胞机制 对手的责任还不是很清楚，但有证据表明，与 阿尔茨海默病(AD)和相关的神经退行性疾病(NDS)。事实上，各种报道 研究表明，艾滋病毒感染者会出现阿尔茨海默病特有的神经病理特征， 包括淀粉样β蛋白(Aβ)斑块的沉积和由 磷酸化牛磺酸(Ptau)。然而，目前尚不清楚这些异常是否有关联 特别是与HIV感染有关，并在患者的神经异常中发挥作用 受手部影响。一个主要的问题是要理解涉及到的分子机制 HIV感染对脑退行性变的影响是缺乏适当的模型来研究其影响 人类大脑中的艾滋病毒以及与NDS相关的病理过程的相互作用。少校 这个项目的目标是全面研究错误折叠的蛋白质聚集体在 HIV感染者的脑和生物液，有或没有手，也与 采用联合抗逆转录病毒疗法(CART)治疗。我们的工作假设是艾滋病毒 感染或使用CART治疗会引发促进错误折叠和早期 容易在NDS中聚集和/或减少清除途径的蛋白质的寡聚 正常情况下会消除这些异常折叠的蛋白质。为了检验这一假设，我们提出了 具体目标如下：(1)错误折叠的蛋白质聚集体的检测和表征 HIV感染者的大脑。(2)检测生物体液中错误折叠的蛋白质聚集体 HIV感染患者尝试开发一种生化分析来帮助手部诊断和 监控其进程。(3)研究HIV感染效应的新型体外模型的建立 在使用实验室产生的类脑器官进行大脑改变时。 在这个项目中产生的发现可能有助于启发错误折叠的假定作用 HIV感染所致神经功能异常中的蛋白质聚集体 AD与相关NDS之间的潜在相互作用与HAND的发病机制。这个项目可能 为建立一种新的手部生化诊断方法及相关模型做出贡献 研究艾滋病毒感染的中枢神经系统效应的系统。

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.