In Vivo Reconstitution Models for NeuroAIDS and Beta-Amyloidosis

针对人类免疫缺陷病毒（HIV）-1感染的抗逆转录病毒疗法（ART）延长并改善了生活质量和寿命。尽管如此，与HIV相关的疾病发病率比比皆是，包括在疾病后期观察到的认知功能障碍（HIV相关痴呆，HAD和轻微认知运动障碍，MCMD等）。因此，随着感染者活到60多岁，他们将更常见地面临神经退行性疾病的蹂躏。目前，人们对诸如阿尔茨海默病（AD）的疾病如何受到慢性病毒感染的影响以及慢性病毒感染如何改变AD的节奏和进展知之甚少。我们推测，慢性神经炎症介导的病毒感染的单核吞噬细胞（MP;血管周围的巨噬细胞和小胶质细胞）可以加速AD的发病。我们建议在HIV感染的大脑中开发β-淀粉样变性的动物模型。我们将特别关注HIV-1和神经炎症介质（如促炎细胞因子和趋化因子）对神经元和星形胶质细胞产生Aj3，小胶质细胞降解Aj3以及Aj3寡聚体形成和沉积在大脑中的作用。这项研究意义重大。因为我们可以评估HIV-1感染的小胶质细胞在AD发病机制中的作用。将通过多方面分析来研究动物模型以表征疾病发病机制，包括神经炎症、Aj3相关的神经病理学、Aj3-淀粉样前体蛋白（APP）加工和聚集以及Aj3降解酶级联。在这份资助申请中提出了两个具体目标。1)研究慢性HIV-1感染对人单核细胞衍生的巨噬细胞（MDM）中Aj3合成和代谢的假定作用; 2）表征持续病毒感染对严重受损免疫缺陷小鼠中β-淀粉样变性的作用，所述严重受损免疫缺陷小鼠颅内表达转基因APP，所述转基因APP与HIV感染的人MDM重组。我们将特别关注病毒蛋白和促炎细胞因子的影响，以及在两个实验范例中调节Aj3合成和清除的细胞内信号传导。本研究对于建立慢性艾滋病患者早期AD发病的临床前模型和阐明其发病机制具有重要意义，对慢性艾滋病患者的预后、预防和治疗具有重要意义。

Anti-retroviral therapy (ART) for human immunodeficiency virus (HIV)-1 infection has prolonged and improved quality and longevity of life. Nonetheless, disease morbidities associated with HIV abound, including cognitive dysfunction (HIV associated dementia, HAD, and minor cognitive movement disorders, MCMD, among others) seen during the later stages of the disease. Thus, as infected people live well into their 60's and beyond they will more commonly face the ravages of neurodegenerative diseases. Currently, it is poorly understood how diseases such as Alzheimer's disease (AD) will be affected by chronic viral infection and how chronic viral infection will alter the tempo and progression of AD. We hypothesize that chronic neuroinflammation mediated by virus-infected mononuclear phagocytes (MP; perivascular macrophages and microglia) can accelerate the onset of AD. We propose developing animal models of beta-amyloidosis in HIV infected brains. We will specifically focus on the role of HIV-1 and neuroinflammation mediators, such as pro-inflammatory cytokines and chemokines, on Aj3 production from neurons and astrocytes, Aj3 degradation by microglia, and Aj3 oligomer formation and deposition in the brain. The study is significant. since we can evaluate the effect of HIV-1-infected microglia on AD pathogenesis. The animal models will be studied by multifaceted analysis to characterize the disease pathogenesis, including neuroinflammation, Aj3-related neuropathology, j3-amyloid precursor protein (APP) processing and aggregation, and Aj3 degrading enzyme cascade. Two specific aims are proposed in this grant application. 1) To investigate the putative roles played by chronic HIV-1 infection on Aj3 synthesis and metabolism in human monocyte-derived macrophages (MDM); 2) To characterize the role of persistent viral infection on beta-amyloidosis in severely compromised immunodeficiency mice expressing transgenic APP intracranially reconstituted with HIV-infected human MDM. We will specifically focus on the effect of viral proteins and pro-inflammatory cytokines, and intracellular signaling on regulation of Aj3 synthesis and clearance in two experimental paradigms. The study is significant in developing a preclinical model and elucidating the disease mechanism for early on set of AD in chronic AIDS patients, which will be useful for their prognosis, prevention, and therapy.