Neuroprotection by IFN-beta in AIDS

描述(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，神经变性的发生是由于HIV-1感染和小胶质细胞和巨噬细胞(M？)的神经毒性免疫刺激。大脑和神经发生的障碍。除了激活M？和小胶质细胞，感染HIV-1会触发包括产生干扰素(IFN)在内的先天免疫反应。虽然干扰素对抗病毒免疫反应很重要，但干扰素的持久表达？在HIV-1暴露中，中枢神经系统(CNS)与认知障碍和炎症性神经病理有关。相比之下，干扰素呢？与控制大脑中的艾滋病毒感染有关。干扰素？诱导在M？和小胶质细胞天然的HIV辅助受体CCR5的配体，如MIP-1？和RANTES，它们抑制HIV-1感染。干扰素？还可诱导神经生长因子(NGF)的表达，具有明显的抗炎作用。我们在初步研究中发现，干扰素？保护大脑皮层神经元免受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降低促炎症和应激相关的p38丝裂原活化蛋白激酶(MAPK)的活性，并以Akt依赖的方式保护大脑皮层神经元免受HIV/gp120的神经毒性。因此，我们建议表征干扰素？的明显神经保护作用。利用体内和体外模型对抗HIV/gp120的毒性。我们假设干扰素？可以通过一系列独特的机制抑制HIV/gp120诱导神经元损伤、损害神经发生和损害记忆和认知，包括诱导神经保护性趋化因子和神经营养性NGF。长期目标是为艾滋病毒相关痴呆寻找新的潜在治疗方法。具体目的是：(1)体内研究是否存在干扰素？在HIV/gp120转基因小鼠模型中防止神经元损伤。(2)体外评价干扰素是否存在相互作用？小胶质细胞还是M？足以防止诱导HIV/gp120神经毒性。(3)探讨干扰素是否存在相互作用？与神经元和星形胶质细胞联合足以保护细胞免受HIV/gp120诱导的小胶质细胞的神经毒性。针对特定目标1，干扰素？将通过鼻腔给药，这在很大程度上允许在将药物输送到大脑的同时绕过血脑屏障。将比较干扰素？转基因小鼠和赋形剂治疗的HIV/gp120转基因小鼠在记忆和认知基础上的行为表现、神经元损伤、神经发生和神经胶质形成。这三个特定的目标都将考验这样一个前提：干扰素？诱导神经保护性β-趋化因子和NGF，增加Akt活性，降低p38MAPK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的损伤。我们还将评估是否存在干扰素？在HIV/gp120存在的情况下，可以保护神经发生、记忆和认知，并减少胶质细胞增生。

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.