Modulating Autophagy to Eradicate HIV-1 from CNS Reservoirs

描述（由申请人提供）：尽管抗逆转录病毒联合治疗导致了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HIV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淀粉样蛋白的小胶质细胞吞噬而增加轻度认知障碍的风险。此外，尽管有一例记录在案的患者在骨髓移植后治愈了艾滋病毒，但尚未制定出能够导致根除病毒的有效策略。在本研究中，我们将研究自噬在保存中枢神经系统（CNS）内HIV储存库中的作用，并确定从这些隐匿部位根除病毒的策略。本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发病的重要机制，并且调节自噬可以抑制HIV并优先杀死HIV感染的细胞。本提案的具体目的是：目的1：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：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，从巨噬细胞、小胶质细胞和星形胶质细胞中根除艾滋病毒；目的3：体外优化在中枢神经系统内靶细胞中根除HIV，使其对神经元的毒性最小；目标4：从静止的T细胞中根除HIV

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.