Neuroprotection by IFN-beta in AIDS

描述（由申请人提供）：感染人类免疫缺陷病毒(HIV)-1可导致痴呆症，目前尚无治疗方法。我们和其他实验室的研究强烈表明，神经变性是HIV-1感染和脑内小胶质细胞和巨噬细胞（M?）的神经毒性免疫刺激以及神经发生损伤的结果。除了激活M？和小胶质细胞一样，HIV-1感染引发了先天免疫反应，包括干扰素（ifn）的产生。虽然IFN对抗病毒免疫反应很重要，但IFN的持续表达？HIV-1暴露的中枢神经系统（CNS）与认知障碍和炎症性神经病理学有关。相比之下，IFN？与大脑中HIV感染的控制有关。干扰素吗?在M？和HIV辅助受体CCR5的小胶质细胞天然配体，如MIP-1？以及抑制HIV-1感染的RANTES。干扰素吗?还能诱导神经生长因子（NGF）的表达，具有明显的抗炎作用。我们在初步研究中发现IFN？保护脑皮质神经元免受HIV/gp120的神经毒性，同时增加RANTES的基线水平。我们还观察到RANTES和MIP-1？通过CCR5降低促炎和应激相关p38丝裂原活化蛋白激酶（MAPK）的活性，并以akt依赖的方式保护脑皮质神经元免受HIV/gp120的神经毒性。因此，我们提出表征干扰素的明显神经保护作用？在体内和体外模型中对HIV/gp120的毒性进行了研究。我们假设IFN？可以抑制HIV/gp120诱导神经元损伤，损害神经发生，损害记忆和认知，通过独特的机制组合，包括诱导神经保护性？趋化因子和神经营养NGF。长期目标是为hiv相关痴呆找到新的潜在治疗方法。具体目的是：(1)研究体内IFN？在HIV/gp120转基因小鼠模型中预防神经元损伤。(2)体外评估IFN？小胶质细胞或M？足以防止诱导HIV/gp120神经毒性。(3)探讨IFN？神经元和星形胶质细胞足以保护细胞免受HIV/gp120诱导的小胶质细胞神经毒性。针对特异性靶标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。记忆和认知为基础的行为表现，神经元损伤，神经发生和胶质瘤将在IFN？与载体处理的HIV/gp120转基因小鼠相比。这三个具体目标都将检验IFN？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/gp120诱导的损伤。我们也会评估IFN？在HIV/gp120存在的情况下，可以维持神经发生、记忆和认知，并减少神经胶质瘤。

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.