Modulating Autophagy to Eradicate HIV-1 from CNS Reservoirs

描述(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的改善，但神经认知障碍仍然是艾滋病毒感染的重要临床并发症。事实上，一些人认为，抗逆转录病毒治疗可能会通过破坏小胶质细胞对淀粉样蛋白的吞噬作用来增加轻微认知障碍的风险。此外，尽管有一例患者在骨髓移植后治愈艾滋病毒的记录在案，但还没有制定出能够根除病毒的有效策略。在拟议的研究中，我们将研究自噬在保存中枢神经系统(CNS)内的艾滋病毒储存库中的作用，并确定从这些神秘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的基础上，这些数据已经确立了自噬是艾滋病毒致病的重要机制，并且自噬的调节可以抑制艾滋病毒并优先杀死艾滋病毒感染的细胞。这项建议的具体目的是：目标1：确定艾滋病毒在调节感染的小胶质细胞和星形胶质细胞自噬中的作用；目标2：通过诱导自噬和杀死艾滋病毒和/或优先杀死感染艾滋病毒的细胞来根除巨噬细胞、小胶质细胞和星形胶质细胞中的艾滋病毒；目标3：在体外优化中枢神经系统内靶细胞的艾滋病毒根除，使其对神经元的毒性最小；目标4：通过 目标5：在人源化的NSG小鼠艾滋病毒脑模型中，通过诱导自噬和长效纳米配方抗逆转录病毒疗法(NanoArt)在体内根除艾滋病毒。这项拨款提案有许多创新之处。首先，通过调节自噬来杀死艾滋病毒和感染艾滋病毒的细胞的策略是创新的，是我的实验室首创的。其次，除了使用药理学试剂通过不同的途径诱导自噬外，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导致杀死HIV。第三，我们将把我们的体外发现转化为一种新颖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的使用相结合，以改善抗逆转录病毒对细胞的传递。第四，我们已经建立了一支杰出的研究团队，将他们在艾滋病毒、巨噬细胞、自噬和神经艾滋病方面的丰富知识结合起来，以解决这一具有挑战性的问题。最后，这一创新方法提供了一种从中枢神经系统和身体其他部位根除艾滋病毒的新战略，如果成功，这一战略有可能适用于所有艾滋病毒感染者。

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.