Astrocytic HIV Nef causes learning impairment via inflammation and TGF signaling

描述（由申请人提供）：本提案解决了一个与美国HIV/AIDS流行日益相关的重要问题：HIV Nef如何导致神经病理学和学习障碍？联合抗逆转录病毒治疗（cART）的成功通过防止艾滋病的进展大大提高了感染后的预期寿命。这一进展使人们更加重视对剩余发病率的管理。尽管艾滋病毒复制的临床管理已将病毒复制控制在可检测水平以下，但艾滋病毒相关神经认知障碍（HAND）的患病率仍在上升。几条线索的证据表明，HIV神经毒素的产生，而不是病毒的复制，是导致这种进展的原因。我们在大鼠身上建立了一个神经病理学模型，模拟了cART病毒控制下的神经病理学。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，星形胶质细胞也会产生Nef。我们发现，在大鼠海马中注入经修饰产生Nef的自体星形胶质细胞后，出现炎症、神经元丢失和学习障碍。我们的初步研究使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。我们的数据表明TGF信号和CCL2在该病理中的作用。我们将从两个方面来解决这个假设。首先，我们将重点确定与学习障碍程度相关的神经元损失的机制和程度。这方面研究的一个主要重点是确定产生我们已经确定的模型结果的因果关系。第二个目的是研究TGF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。这一目的将通过一系列原代细胞和细胞系的体外实验来探讨TGF信号在Nef神经毒性中的需求。本研究结果将有助于我们进一步了解神经毒性和学习障碍的机制。这些研究的完成有望确定未来治疗开发的生物学靶点，以解决艾滋病毒临床管理的下一个前沿问题。既然抑制复制已经把HIV感染变成了一种慢性疾病，而不是一种必然的死亡，像HAND这样的疾病的性质和持续时间的变化需要新的治疗方法，而目前还没有。

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.