Modulating Autophagy to Eradicate HIV-1 from CNS Reservoirs

描述（由申请人提供）：尽管联合抗逆转录病毒治疗已导致显著的病毒学抑制和免疫功能改善，但神经认知障碍仍然是HIV感染的重要临床并发症。事实上，有些人认为抗逆转录病毒治疗可能会通过破坏小胶质细胞对β-淀粉样蛋白的吞噬作用来增加轻微认知障碍的风险。此外，虽然有一个记录的情况下，艾滋病毒治愈的患者骨髓移植后，没有有效的策略已经开发出来，可以导致根除病毒。在拟议的研究中，我们将研究自噬在中枢神经系统（CNS）内保存HIV储库中的作用，并确定从这些隐匿部位根除病毒的策略。这项研究将建立在我们大量的初步数据基础上，这些数据已经确定自噬是HIV发病机制的重要机制，并且自噬的调节可以抑制HIV并优先杀死HIV感染的细胞。本提案的具体目的是：目的1：鉴定HIV在受感染的小胶质细胞和星形胶质细胞中调节自噬的作用;目的2：通过诱导自噬和杀死HIV和/或优先杀死HIV感染的细胞，从巨噬细胞、小胶质细胞和星形胶质细胞中根除HIV;目的3：CNS内靶细胞中HIV根除的体外优化，导致对神经元的毒性最小;目的4：通过以下途径从静息T细胞中根除HIV 诱导自噬和优先杀死HIV感染的细胞;和目的5：在HIV的人源化NSG小鼠脑模型中通过诱导自噬结合长效纳米配制抗逆转录病毒疗法（nanoART）体内根除HIV。这项赠款提案有许多创新之处。首先，调节自噬以杀死HIV和HIV感染细胞的策略是创新的，并且是由我的实验室开创的。第二，除了使用药物通过不同途径诱导自噬外，我们还将使用一种创新的tat-Beclin 1肽，它可以有效地进入细胞并杀死HIV。第三，我们将把我们在体外的发现转化为一种新的和创新的小鼠模型系统，以在体内测试我们的发现，并将我们的方法与纳米ART的使用结合联合收割机，以改善抗逆转录病毒药物向细胞的递送。第四，我们已经建立了一个杰出的研究人员团队，将他们对艾滋病毒、巨噬细胞、自噬和神经艾滋病的大量知识联合收割机结合起来，以解决这一具有挑战性的问题。最后，这种创新的方法提供了一种从CNS以及身体其他部位根除HIV的新策略，如果成功，有可能应用于所有HIV感染者。

DESCRIPTION (provided by applicant): Although combination antiretroviral therapy has led to significant virologic suppression and improvement in immune function, neurocognitive impairment remains an important clinical complication of HIV infection. In fact, some have suggested that antiretroviral treatment might enhance the risk of minor cognitive impairment through the disruption of microglial phagocytosis of �-amyloid. Moreover, although there has been a single documented case of a HIV cure in a patient following bone marrow transplantation, no effective strategy has been developed that can leads to eradication of virus. In the research proposed, we will examine the role of autophagy in the preservation of HIV reservoirs within the central nervous system (CNS) and identify strategies to eradicate virus from these occult sites. This research will build upon our considerable preliminary data that has established autophagy as an important mechanism of HIV pathogenesis and that modulation of autophagy can inhibit HIV and preferentially kill HIV infected cells. The Specific Aims of this proposal are: Aim 1: Identification of role of HIV in the modulation of autophagy in infected microglia and astrocytes; Aim 2: Eradication of HIV from macrophages, microglial cells and astrocytes through the induction of autophagy and killing of HIV and/or preferential killing of HIV-infected cells; Aim 3: In vitro optimization of HIV eradication in target cells within the CNS resulting in the least toxicity to neurons; Aim 4: Eradication of HIV from resting T- cells through the induction of autophagy and preferential killing of HIV-infected cells; and Aim 5: In vivo eradication of HIV through the induction of autophagy combined with long-acting nano-formulated antiretroviral therapy (nanoART) in a humanized NSG mouse brain model of HIV. There are many innovative aspects to this grant proposal. First, the strategy of modulating autophagy to kill HIV and HIV-infected cells is innovative and has been pioneered by my laboratory. Second, in addition to using pharmacologic agents to induce autophagy through different pathways, we will use an innovative tat-Beclin 1 peptide that effectively enters cells an leads to the killing of HIV. Third, we will translate our in vitro findings into a novel and innovaive mouse model system to test our findings in vivo and combine our approach with the use of nano-ART to improve antiretroviral delivery to cells. Fourth, we have established an outstanding team of investigators to combine their considerable knowledge of HIV, macrophages, autophagy and NeuroAIDS in order to address this challenging problem. Finally, this innovative approach provides a novel strategy to eradicate HIV from the CNS as well as the rest of the body that if successful has the potential to be applied to all HIV-infected persons.