Modulating Autophagy to Eradicate HIV-1 from CNS Reservoirs

调节自噬以消除中枢神经系统储库中的 HIV-1

基本信息

批准号：
9261606
负责人：
STEPHEN A SPECTOR
金额：
$ 38.37万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261606
关键词：
Address Amyloid Anti-Retroviral Agents Applications Grants Astrocytes Autophagocytosis Biological Models Biological Preservation Blood Circulation Bone Marrow Transplantation Brain CD4 Positive T Lymphocytes Cells Clinical Communicable Diseases Complication Data Down-Regulation Goals HIV HIV Infections HIV-1 Immune Impaired cognition In Vitro Infection Knowledge Laboratories Microglia Minor Modeling Molecular Mus Myelogenous Nebraska Neuraxis Neurocognitive Deficit Neurons Outcome Pathogenesis Pathway interactions Patients Peptides Peripheral Persons Phagocytosis Pharmacology Play Population Property Research Research Personnel Rest Risk Role Signal Transduction Site T-Lymphocyte Testing Toxic effect Translating Universities Viral Viral reservoir Virus Virus Diseases antiretroviral therapy base cell type efficacy testing experimental study humanized mouse immune function improved in vivo innovation killings lymph nodes macrophage mouse model nano neuroAIDS neuroinflammation neurotoxicity novel novel strategies prevent public health relevance targeted treatment virology

项目摘要

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.

描述（由应用提供）：尽管抗逆转录病毒疗法的组合导致了显着的病毒学抑制和免疫功能的改善，但神经认知障碍仍然是HIV感染的重要临床并发症。实际上，一些人建议抗逆转录病毒治疗可能会通过破坏淀粉样蛋白的小胶质细胞吞噬作用来增加严重认知障碍的风险。此外，尽管在骨髓移植后患者中有一个记录在患者中治愈的艾滋病毒治疗的病例，但尚未制定有效的策略，可以导致病毒辐射。在提出的研究中，我们将研究自噬在中枢神经系统（CNS）中保存HIV储藏中的作用，并从这些神秘部位确定放射性病毒的策略。这项研究将基于我们的考虑初步数据，该数据已确立自噬是HIV发病机理的重要机制，并且自噬的调节可以抑制HIV并优先杀死HIV感染的细胞。该提案的具体目的是：目标1：识别艾滋病毒在受感染的小胶质细胞和星形胶质细胞中自噬调节中的作用； AIM 2：通过诱导自噬和杀死HIV和/或首选的HIV感染细胞杀死HIV，从巨噬细胞，小胶质细胞和星形胶质细胞中消除HIV；目标3：在中枢神经系统内靶细胞中艾滋病毒根除的体外优化，导致对神经元的毒性最少；目标4：从静止的T细胞中根除艾滋病毒诱导自噬和优先杀死HIV感染的细胞；和目标5：通过诱导自噬结合长期纳米形成的抗逆转录病毒疗法（NANOART）在人源化的HIV的NSG NSG小鼠脑模型中，消除了HIV的体内消除HIV。该赠款提案有许多创新的方面。首先，调节自噬杀死HIV和感染HIV的细胞的策略是创新的，并且已由我的实验室策划。其次，除了使用药物通过不同的途径诱导自噬外，我们还将使用创新的tat-beclin 1胡椒，可有效进入细胞，导致杀死HIV。第三，我们将我们的体外发现转化为一种新颖而创新的小鼠模型系统，以在体内测试我们的发现，并将方法与使用纳米ART的方法相结合，以改善抗逆转录病毒递送到细胞。第四，我们建立了一支杰出的调查人员团队，以结合他们对艾滋病毒，巨噬细胞，自噬和神经辅助的考虑知识，以解决这个挑战问题。最后，这种创新的方法为中枢神经系统以及身体其他部位提供了一种新颖的策略，即如果成功的人有可能将其应用于所有受HIV感染的人。