Neuroprotection by IFN-beta in AIDS

描述（由申请人提供）：人类免疫缺陷病毒（HIV）-1感染可诱发痴呆，目前尚无治疗方法。我们和其他实验室的研究强烈表明，神经退行性变的发生是HIV-1感染和小胶质细胞和巨噬细胞（M？）以及神经发生受损除了激活M？和小胶质细胞，HIV-1感染触发先天免疫反应，包括干扰素（IFN）的产生。虽然干扰素是重要的抗病毒免疫反应，持久表达的干扰素？在HIV-1暴露的中枢神经系统（CNS）中，与认知障碍和炎性神经病理学有关。相反，IFN？与控制大脑中的艾滋病毒感染有关。干扰素？在M？和HIV辅助受体CCR 5的小胶质细胞天然配体，如MIP-1？和抑制HIV-1感染的RANTES。干扰素？还诱导神经生长因子（NGF）的表达并具有显著的抗炎作用。我们在初步研究中发现，干扰素？在增加RANTES的基线水平的同时保护皮质神经元免受HIV/gp 120的神经毒性。我们还观察到，RANTES和MIP-1？通过CCR 5降低促炎和应激相关的p38丝裂原活化蛋白激酶（MAPK）的活性，并以Akt依赖的方式保护皮质神经元免受HIV/gp 120的神经毒性。因此，我们建议表征IFN？使用体内和体外模型对抗HIV/gp 120毒性。我们假设IFN？可以通过独特的机制组合抑制HIV/gp 120诱导神经元损伤和损害神经发生并损害记忆和认知，包括诱导神经保护性？趋化因子和神经营养性NGF。长期目标是为HIV相关痴呆症找到新的潜在治疗方法。具体目的是：（1）在体内研究IFN？预防HIV/gp 120转基因小鼠模型中的神经元损伤。(2)在体外评估是否干扰素的相互作用？小胶质细胞还是M足以防止HIV/gp 120神经毒性的诱导。(3)探讨IFN？神经元和星形胶质细胞足以保护细胞免受HIV/gp 120诱导的小胶质细胞神经毒性。对于特异性目标1，IFN？将通过鼻内途径给药，这在很大程度上允许绕过血脑屏障，同时将药物输送到大脑。将在IFN？中比较基于记忆和认知的行为表现、神经元损伤、神经发生和神经胶质增生与载体处理的HIV/gp 120转基因小鼠相比。所有这三个具体目标将测试的前提是，干扰素？诱导神经保护？趋化因子和NGF，增加Akt的活性，降低p38 MAPK和糖原合成酶激酶（GSK）32的活性以及tau的过度磷酸化，从而保护神经元及其树突和突触免受HIV/gp 120诱导的损伤。我们还将评估是否IFN？在HIV/gp 120存在的情况下，可以保护神经发生、记忆和认知，并减少神经胶质增生。

DESCRIPTION (provided by applicant): Infection with Human Immunodeficiency virus (HIV)-1 can induce dementia for which currently no treatment is available. Research in our and other laboratories strongly suggests that neurodegeneration occurs as a consequence of HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (M?) in the brain and impairment of neurogenesis. Beyond activation of M? and microglia, infection with HIV-1 triggers an innate immune response that includes production of interferons (IFNs). While IFNs are important for an anti-viral immune response, the lasting expression of IFN? in the HIV-1 exposed central nervous system (CNS) has been connected to cognitive impairment and inflammatory neuropathology. In contrast, IFN? has been implicated in the control of HIV infection in the brain. IFN? induces in M? and microglia natural ligands of the HIV coreceptor CCR5, such as MIP-1??? and RANTES, which inhibit HIV-1 infection. IFN? also induces the expression of nerve growth factor (NGF) and has pronounced anti-inflammatory effects. We found in preliminary studies that IFN? protected cerebrocortical neurons against neurotoxicity of HIV/gp120 while increasing baseline levels of RANTES. We also observed that RANTES and MIP-1? via CCR5 reduce the activity of the pro-inflammatory and stress-related p38 mitogen activated protein kinase (MAPK) and protect cerebrocortical neurons against neurotoxicity of HIV/gp120 in an Akt-dependent manner. Therefore, we propose to characterize the apparent neuroprotective effect of IFN? against toxicity of HIV/gp120 using in vivo and in vitro models. We hypothesize that IFN? can inhibit HIV/gp120 from inducing neuronal damage and impairing neurogenesis and compromising memory and cognition by a unique combination of mechanisms, comprising the induction of neuroprotective ?-chemokines and neurotrophic NGF. The long-term objectives are to find new potential treatments for HIV-associated dementia. The specific aims are: (1) To study in vivo whether IFN? prevents neuronal damage in a HIV/gp120 transgenic mouse model. (2) To assess in vitro whether the interaction of IFN? with microglia or M? suffices to prevent induction of HIV/gp120 neurotoxicity. (3) To investigate whether the interaction of IFN? with neurons and astrocytes suffices to protect the cells against HIV/gp120-induced neurotoxicity of microglia. For Specific Aim 1, IFN? will be administered via an intranasal route, which largely allows bypassing the blood brain barrier while delivering the drug to the brain. Memory and cognition-based behavioral performance, neuronal injury, neurogenesis and gliosis will be compared in IFN?- versus vehicle-treated HIV/gp120-transgenic mice. All three Specific Aims will test the premise that IFN? induces neuroprotective ?-chemokines and NGF, increases activity of Akt, reduces activity of p38 MAPK and glycogen synthase kinase (GSK) 32 and hyperphosphorylation of tau, and thus protects neurons and their dendrites and synapses from HIV/gp120-induced damage. We will also assess whether IFN? can preserve neurogenesis, memory and cognition and reduce gliosis in the presence of HIV/gp120.