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

• 批准号: 8656828
• 负责人: STEPHEN A SPECTOR
• 金额: $ 38.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656828
• 关键词: AIDS neuropathy; 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; Impairment; In Vitro; Infection; Knowledge; Laboratories; Microglia; Minor; Modeling; Molecular; Mus; Myelogenous; Nebraska; Neuraxis; Neurocognitive; Neurons; Outcome; Pathogenesis; Pathway interactions; Patients; Peptides; Peripheral; Persons; Phagocytosis; Play; Population; Property; Research; Research Personnel; Rest; Risk; Role; Signal Transduction; Site; T-Lymphocyte; Testing; Toxic effect; Translating; Universities; Viral; Virus; Virus Diseases; antiretroviral therapy; base; cell type; efficacy testing; immune function; improved; in vivo; innovation; killings; lymph nodes; macrophage; mouse model; nano; neuroinflammation; neurotoxicity; novel; novel strategies; prevent; public health relevance; research study

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（由申请人提供）：尽管联合抗逆转录病毒治疗已导致显着的病毒学抑制和免疫功能改善，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增加轻微认知障碍的风险。通过破坏小胶质细胞的吞噬作用而造成损害 ¿此外，尽管有一个记录在案的患者在骨髓移植后治愈艾滋病毒的病例，但尚未开发出可以根除病毒的有效策略。在拟议的研究中，我们将研究其作用。这项研究将建立在我们大量的初步数据基础上，这些数据已确定自噬是艾滋病毒发病机制的重要机制和调节机制。自噬可以抑制 HIV 并优先杀死 HIV 感染的细胞。该提案的具体目标是： 目标 1：确定 HIV 在受感染的小胶质细胞和星形胶质细胞自噬调节中的作用；目标 2：从巨噬细胞、小胶质细胞中根除 HIV。目标 3：体外优化靶标中的 HIV 根除；目标 4：通过静息 T 细胞消除 HIV 诱导自噬并优先杀死 HIV 感染细胞；目标 5：在 HIV 人源化 NSG 小鼠脑模型中，通过诱导自噬结合长效纳米抗逆转录病毒疗法 (nanoART) 体内消灭 HIV。这项资助提案有很多创新之处，首先，调节自噬杀死 HIV 和 HIV 感染细胞的策略是创新的，并且是我的实验室首创的。使用药物通过不同途径诱导自噬，我们将使用创新的 tat-Beclin 1 肽，该肽可有效进入细胞并杀死 HIV。第三，我们将把我们的体外研究结果转化为一种新颖的创新小鼠模型系统。第四，我们建立了一支优秀的研究团队，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。最后，这种创新方法提供了一种从中枢神经系统以及身体其他部位根除艾滋病毒的新策略，如果成功的话，有可能适用于所有艾滋病毒感染者。