In Vivo Reconstitution Models for NeuroAIDS and Beta-Amyloidosis

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。然而，与艾滋病毒有关的疾病发病率很高，包括在疾病后期出现的认知功能障碍(艾滋病毒相关性痴呆症和轻微认知运动障碍，等等)。因此，随着感染者活到60岁及以上的S，他们将更常见地面临神经退行性疾病的蹂躏。目前，人们对阿尔茨海默病(AD)等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。我们假设由病毒感染的单核巨噬细胞(MP；血管周围巨噬细胞和小胶质细胞)介导的慢性神经炎可以加速AD的发生。我们建议建立HIV感染大脑中的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寡聚体的形成和在脑中沉积的作用。这项研究意义重大。因此，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。这些动物模型将通过多方面的分析来表征疾病的发病机制，包括神经炎症、AJ3相关的神经病理、J3-淀粉样前体蛋白(APP)的加工和聚集以及AJ3降解酶的级联。在这项赠款申请中提出了两个具体目标。1)研究HIV-1慢性感染对人单核细胞来源的巨噬细胞(MDM)AJ3合成和代谢的影响；2)研究持续病毒感染对表达由HIV感染的人MDM重组的转基因APP免疫缺陷小鼠的β淀粉样变性的影响。我们将在两个实验范例中特别关注病毒蛋白和致炎细胞因子以及细胞内信号对AJ3合成和清除的调节作用。本研究对建立慢性艾滋病患者早期阿尔茨海默病的临床前模型和阐明其发病机制具有重要意义，对其预后、预防和治疗具有一定的指导意义。

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.