Astrocytic HIV Nef causes learning impairment via inflammation and TGF signaling

描述(由申请人提供)：这项建议解决了与美国艾滋病毒/艾滋病流行日益相关的一个关键问题：艾滋病毒Nef如何导致神经病理和学习障碍？联合抗逆转录病毒疗法(CART)的成功阻止了艾滋病的进展，极大地延长了感染后的预期寿命。这一进展使人们更加重视对剩余疾病的管理。尽管对艾滋病毒复制的临床管理已将病毒复制控制在可检测到的水平以下，但与艾滋病毒相关的神经认知障碍(HAND)的患病率似乎越来越高。有几条证据表明，导致这种进展的原因是艾滋病毒神经毒素的产生，而不是病毒的复制。我们在大鼠身上开发了一种Nef神经病理学模型，该模型模拟了CART病毒控制环境中仍然存在的神经病理学。NEF是一种已知的HIV神经毒素，即使在没有病毒复制的情况下，也是由星形胶质细胞产生的。我们发现，将经过修饰产生Nef的自体星形胶质细胞注入海马区的大鼠表现出炎症、神经元丢失和学习障碍。我们的初步研究导致我们提出了一个假设，即Nef驱动炎症，导致神经元凋亡和学习障碍。我们的数据提示转化生长因子信号和CCL2在这一病理过程中所起的作用。我们将从两个方面阐述这一假说。在我们的模型中，第一个重点是确定神经元丢失的机制和程度与学习障碍程度的关系。这一目标中研究的一个主要焦点是确定在我们已经确定的模型中产生结果的因果关系。第二个目的是研究转化生长因子信号在星形胶质细胞表达Nef引起的炎症和神经毒性中的机制作用。这一目标将通过一系列原代细胞和细胞系的体外实验来实现，以探讨转化生长因子信号在Nef神经毒性中的需求。这一建议的结果将推动我们理解Nef神经毒性和学习障碍的机制。这些研究的完成预计将为未来治疗的发展确定生物目标，以解决艾滋病毒临床管理的下一个前沿。既然对复制的抑制已经将艾滋病毒感染变成了一种慢性病，而不是判处一定的死亡，手部等疾病不断变化的性质和持续时间需要新的疗法，而目前还不存在这种疗法。

DESCRIPTION (provided by applicant): This proposal addresses a vital question of increasing relevance for the US HIV/AIDS epidemic: How does HIV Nef cause neuropathology and learning impairment? The success of combined antiretroviral therapy (cART) has greatly increased the life expectancy after infection by preventing progression to AIDS. This advance has resulted in greater emphasis on managing remaining morbidities. Even as clinical management of HIV replication has resulted in control of viral replication to below detectable levels, HIV associated neurocognitive disorders (HAND) appear with increasing prevalence. Several lines of evidence point toward production of HIV neurotoxins, rather than viral replication, as the cause of this progression. We developed a model of Nef neuropathology in rats that mimics the neuropathology that remains in the setting of viral control by cART. Nef is a known HIV neurotoxin that is produced by astrocytes even in the absence of viral replication. We found that rats infused into the hippocampus with autologous astrocytes modified to produce Nef showed inflammation, neuronal loss, and learning impairment. Our preliminary studies led us to propose a hypothesis that Nef drives inflammation leading to neuronal apoptosis and learning impairment. Our data suggest roles for TGF signaling and CCL2 in this pathology. We will address the hypothesis in two aims. The first will focus on identifying the mechanism and extent of neuron loss in relation to the degree of learning impairment in our model. A major focus of the studies in this aim is to identify the cause and effect relationships that produce the outcomes in the model we have already identified. The second aim will investigate the mechanistic role for TGF signaling in the inflammation and neurotoxicity caused by astrocyte expression of Nef. This aim will be accomplished through a series of in vitro experiments with primary cells and cell lines to probe the requirement of TGF signaling in Nef neurotoxicity. The outcomes of this proposal will move us forward in understanding the mechanism of Nef neurotoxicity and learning impairment. Completion of these studies is expected to identify biological targets for development of future treatments to address the next frontier in HIV clinical management. Now that suppression of replication has changed HIV infection to a chronic illness rather than a sentence of certain death, the changing nature and duration of morbidities like HAND require novel therapies where none currently exist.