The HIV-Osteopontin-HAND Triad: Inflammation and Neuronal Injury in the Brain

即使在接受主动抗逆转录病毒治疗(ART)的艾滋病毒感染者中，低水平的病毒复制和 炎症持续存在于外周和中枢神经系统(CNS)。艾滋病毒很早就进入了大脑 有令人信服的证据表明，大脑是艾滋病毒的假定储存库，这是导致 神经致病后遗症。事实上，即使接受抗逆转录病毒治疗，手部疾病的患病率和发病率仍然很高。 虽然在了解高病毒条件下手部的病理生理学方面取得了进展 负荷、宿主对低水平慢性全身感染的炎症反应以及这是如何加剧的 大脑中的神经元损伤和功能障碍尚不完全清楚。骨桥蛋白(OPN)--早期标志物 发炎的可能性正在上升。OPN可能是神经元之间关键的细胞间信号连接物， 中枢神经系统的巨噬细胞/小胶质细胞和星形胶质细胞。我们和其他小组发现，OPN在 手，即使是那些正在接受治疗的人。OPN在星形胶质细胞、小胶质细胞和神经元中均有显著表达 手。因此，OPN随着艾滋病毒感染的增加而增加。这些发现表明OPN是一种推定的 手头有神经致病过程的贡献者。OPN和HIV之间存在反馈环路。事实上，我们 表明病毒基因表达与OPN的诱导有很强的相关性。击倒OPN in 巨噬细胞导致HIV产生减少50%，这表明这种细胞因子刺激病毒 复制。事实上，抑制OPN可以阻止HIV在巨噬细胞中的转录和复制。我们的发现 研究表明，骨桥蛋白通过核因子-B和通过激活骨桥蛋白受体、整合素和 CD44。在巨噬细胞中，OPN是丝裂原活化蛋白激酶(MAPK)下游激活所必需的， 先天的和炎症的途径，牵连在手中。总而言之，我们的数据表明OPN是一种 中枢神经系统细胞中HIV复制和促炎信号的重要调节因子。因此，它 我们必须了解OPN信号和下游炎症级联反应，以便 开发新的治疗干预措施。我们的中心假设是，在系统性艾滋病毒的背景下 感染，OPN在激活的巨噬细胞/小胶质细胞、星形胶质细胞和神经元中的表达促进整合素和 CD44信号级联导致慢性炎症和随后的神经元损伤。三管齐下 我们的假设将被用来探索：1)在体内，使用HIV感染的NOD-SCID IL-2R 移植人hCD34+的小鼠。在这个模型中，手部可以看到几个关键的神经病理特征 观察到，它允许持续的艾滋病毒复制，小鼠可以用抗病毒药物治疗，2)在体外，使用 原代巨噬细胞、神经细胞和星形胶质细胞培养以解构分子机制，以及3)ex 活体实验，使用人脑死后组织来验证实验结果。我们预计新的 所获得的知识将为未来旨在减轻神经元和认知损伤的翻译研究奠定基础 在手中。这一点尤其重要，因为到目前为止，还没有确定可行的辅助治疗方法。

Even in HIV-infected individuals on active anti-retroviral therapy (ART), low-level viral replication and inflammation persists in both the periphery and in the central nervous system (CNS). HIV enters the brain early and there is compelling evidence that the brain is a putative reservoir for HIV that is responsible for the neuropathogenic sequelae. Indeed, even with ART, the prevalence and incidence of HAND remains high. While progress has been made in understanding the pathophysiology of HAND under conditions of high viral load, the hosts’ inflammatory responses to low-level chronic systemic infection and how this exacerbates neuronal injury and dysfunction in the brain are incompletely understood. Osteopontin (OPN), an early marker of inflammation is elevated in HAND. OPN may be a key intercellular signaling linker between neurons, macrophages/microglia and astrocytes in the CNS. We, and other groups, found that OPN is increased in HAND, even in those on therapy. OPN is significantly expressed in astrocytes, microglia and neurons in HAND. Thus, OPN increases in response to HIV infection. These findings suggest that OPN is a putative contributor to neuropathogenic processes in HAND. A feedback loop exists between OPN and HIV. Indeed, we showed a strong relationship between viral gene expression and the induction of OPN. Knockdown of OPN in macrophages led to a 50% reduction in HIV production, suggesting that this cytokine stimulates viral replication. Indeed inhibition of OPN blocks HIV transcription and replication in macrophages. Our findings show that OPN enhances HIV replication through NF-B and via activation of OPN receptors, integrins and CD44. In macrophages, OPN is required for the downstream activation of mitogen-activated kinases (MAPKs), innate and inflammatory pathways, implicated in HAND. Together, our data suggests that OPN is an important regulator of both HIV replication and proinflammatory signaling in cells of the CNS. Hence, it is critical that we understand OPN signaling and downstream inflammatory cascades in order to develop new therapeutic interventions. Our central hypothesis is that in the context of systemic HIV infection, OPN expression in activated macrophages/microglia, astrocytes and neurons promotes integrin and CD44 signaling cascades resulting in chronic inflammation and subsequent injury of neurons. A three-pronged approach will be used to explore our hypothesis: 1) in vivo, using HIV-infected NOD-scid IL-2R mouse engrafted with human hCD34+. In this model, several key neuropathological hallmarks seen in HAND are observed, it allows persistent HIV replication, and mice can be treated with antivirals, 2) in vitro, using primary macrophage, neuronal, and astrocytic cultures to deconstruct the molecular mechanisms, and 3) ex vivo, using human brain postmortem tissue to validate experimental findings. We expect that the new knowledge gained will allow for future translational studies aimed at alleviating neuronal and cognitive damage in HAND. This is especially important as to date, no viable adjunctive therapy has yet been identified.