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。一些证据强烈表明，神经变性是由于HIV-1感染和脑中小胶质细胞和巨噬细胞（MΦ）的神经毒性免疫刺激以及神经发生受损而发生的。HIV-1还引发先天免疫反应，包括产生干扰素（IFN）。IFNβ参与控制大脑中的HIV感染，并具有显著的抗炎作用。在上一个资助期，我们发现：首先，HIV/gp 120转基因（tg）小鼠的CNS基因表达分析显示有限的IFN应答。HIV/gp 120 tg脑在1.5月龄时瞬时表达IFNβ，但在神经病理学和行为障碍发生时，3或6月龄时不表达。第二，我们发现四周鼻内（i.n.）从3.5月龄开始的IFNβ治疗完全防止了HIV/gp 120 tg小鼠的神经元损伤。第三，IFNβ通过早期诱导CCL 3保护体外神经元免受HIV/gp 120的神经毒性，这在小胶质细胞存在时最有效。在本更新申请中，我们拟表征i）内源性IFN应答的贡献和ii）IFNα/β受体1（IFNAR 1）和IFN刺激基因（ISG）在IFNβ对HIV-1或gp 120毒性的神经保护中的细胞类型特异性作用。我们假设IFNβ可以通过诱导神经保护性IFN刺激基因（ISG）如IRF 1和CCL 3以及抑制炎症来保护神经元免受HIV-1/gp 120诱导的毒性并保护行为表现。具体目标是：（1）在体内研究内源性IFNβ对HIV/gp 120转基因小鼠神经元损伤的影响及鼻内IFNβ治疗的反应。(2)在体内研究小胶质细胞或星形胶质细胞或神经元的干扰素α/β受体1（IFNAR 1）是否是IFNβ对抗HIV/gp 120毒性的神经保护所必需的。(3)评估外源性IFNβ的持续供应是否可以通过诱导抗病毒ISG的子集来限制HIV-1感染和MΦ的相关神经毒性。对于特定目的1和2，IFNβ 将通过鼻内途径给药，这样可以绕过血脑屏障，同时将药物输送到大脑。将在缺乏内源性IFNβ或其受体IFNAR 1的IFNβ与溶剂处理的HIV/gp 120转基因小鼠中比较基于记忆和认知的行为表现、神经元损伤和神经胶质增生。我们还将评估哪些神经细胞类型需要与IFNβ相互作用，以保留记忆和认知并减少HIV/gp 120存在下的神经胶质增生。具体目标3将使用RNA测序来定义神经毒性HIV-1感染的MΦ的RNA特征，并将测试外源性IFNβ可以克服HIV-1引起的抗病毒因子的下调和神经毒素的产生的前提。所有三个特定目的将测试以下前提：IFNβ诱导神经保护性β-趋化因子，增加Akt活性并降低p38 MAPK活性，从而保护神经元及其树突和突触免受HIV或gp 120诱导的小胶质细胞和MΦ毒性。

 DESCRIPTION (provided by applicant): Infection with Human Immunodeficiency virus (HIV)-1 can induce dementia for which currently no treatment is available. Several lines of evidence strongly suggest that neurodegeneration occurs as a consequence of HIV-1 infection and neurotoxic immune stimulation of microglia and macrophages (MΦ) in the brain and impairment of neurogenesis. HIV-1 also triggers an innate immune response that includes production of interferons (IFNs). IFNβ has been implicated in the control of HIV infection in the brain and has pronounced anti-inflammatory effects. In the previous funding period we found: First, a CNS gene expression analysis of HIV/gp120 transgenic (tg) mice revealed a limited IFN response. HIV/gp120tg brains transiently expressed IFNβ at 1.5 but not 3 or 6 months of age when neuropathology and behavioral impairment developed. Second, we found that a four-week intranasal (i.n.) IFNβ treatment starting at 3.5 months of age completely prevented neuronal damage in HIV/gp120tg mice. Third, IFNβ protected neurons in vitro against neurotoxicity of HIV/gp120 by early induction of CCL3, which occurred most efficiently in the presence of microglia. In this renewal application we propose to characterize i) the contribution of the endogenous IFN response and ii) the cell type-specific role of IFNα/β receptor 1 (IFNAR1) and IFN-stimulated genes (ISGs) in neuroprotection by IFNβ against toxicity of HIV-1 or gp120. We hypothesize that IFNβ can protect neurons from HIV-1/gp120 induced toxicity and preserve behavioral performance by a mechanisms, comprising induction of neuroprotective IFN-stimulated genes (ISG) such as IRF1 and CCL3 and inhibition of inflammation. The specific aims are: (1) To study in vivo how endogenous IFNβ affects neuronal damage in a HIV/gp120 transgenic mouse model and the animals' response to intranasal IFNβ treatment. (2) To examine in vivo whether the interferon α/β receptor 1 (IFNAR1) of microglia or astrocytes or neurons are necessary for neuroprotection by IFNβ against toxicity of HIV/gp120. (3) To assess whether a continuous supply of exogenous IFNβ can restrict HIV-1 infection and the associated neurotoxicity of MΦ via induction of a subset of anti-viral ISGs. For Specific Aims 1 and 2, IFNβ will be administered via an intranasal route, which allows bypassing the blood brain barrier while delivering the drug to the brain. Memory and cognition-based behavioral performance, neuronal injury and gliosis will be compared in IFNβ- versus vehicle-treated HIV/gp120-transgenic mice lacking endogenous IFNβ or its receptor IFNAR1. We will also assess which neural cell type(s) are required to interact with IFNβ in order to preserve memory and cognition and to reduce gliosis in the presence of HIV/gp120. Specific Aim 3 will define an RNA signature of neurotoxic HIV-1 infected MΦ using RNA-sequencing and will test the premise that exogenous IFNβ can overcome the down- regulation of antiviral factors and production of neurotoxins by HIV-1. All three Specific Aims will test the premise that IFNβ induces neuroprotective β-chemokines, increases activity of Akt and reduces activity of p38 MAPK, and thus protects neurons and their dendrites and synapses from HIV or gp120-induced toxicity of microglia and MΦ.