Elucidating the role of Ephrin-b1 in Interferon Beta (IFN-beta) mediated neuroprotection in HIV associated neurocognitive disorder (HAND)

项目摘要 全世界有3700万人被诊断患有人类免疫缺陷病毒（HIV）。在这3700万人中， 据估计，15-55%的HIV感染者会出现HIV相关的神经认知障碍（HAND）。先前 我们和其他实验室的工作确定了干扰素β（IFNβ）和抗病毒1型干扰素的短暂增加， 在HIVgp 120转基因小鼠和SIV模型中出现任何行为或神经病理学体征之前， 提示IFNβ在早期HIV感染中具有神经保护作用。我们之前已经证明， 用IFNβ鼻内暴露HIVgp 120 tg动物足以提供神经保护。初步数据 描述了HIVgp 120病毒蛋白和IFNβ调节重要细胞表面的能力 跨膜配体ephrin-B1。神经元ephrin-B1已经被很好地研究，并与 神经元发育，NMDA受体的募集和突触可塑性主要通过其信号传导， EphB受体。然而，肝配蛋白-B1在HIV中的功能作用，特别是小胶质细胞特异性肝配蛋白-B1， 被很好地描述了。 我们的初步数据鉴定了EphB 2 mRNA（主要受体之一）的统计学显著上调。 的ephrin-B1）在大脑病理的HIV+患者的皮质。此外，我们描述了显着的逆 HIV阳性患者大脑皮层ephrin-B1 mRNA与神经认知功能评分的相关性 和抑制神经元基因表达。在转基因NeuroHIV小鼠体内模型中，我们发现在皮质中， 和海马，gp 120的存在以细胞特异性方式上调ephrin-B1蛋白表达， 包括小胶质细胞。用IFNβ治疗略微降低肝配蛋白-B1表达，但显著降低肝配蛋白-B1表达。 ephrin-B1从小胶质细胞表面脱落。我们认为，EphB 2和ephrin-B1之间增强的信号传导在肝细胞中起重要作用。 HIV+患者的CNS可能导致炎症反应增强以及不必要的突触修剪， 切除小胶质细胞肝配蛋白-B1将部分减轻炎症和突触修剪。这项建议旨在 确定调节小胶质细胞ephrin-B1对小胶质细胞状态和神经元健康的功能后果 in the context背景of HIV艾滋病毒.

Project Abstract 37 million people worldwide are diagnosed with Human Immunodeficiency Virus (HIV). Of these 37 million, an estimated 15-55% of people living with HIV develop HIV-associated neurocognitive disorder (HAND). Previous work in ours and other labs identifies a transient increase of interferon beta (IFNβ), and antiviral type 1 interferon, preceding any behavioral or neuropathological signs in the HIVgp120 transgenic mouse and SIV models, suggesting a neuroprotective role for IFNβ in early HIV infection. We have previously shown that exogenous intranasal exposure of HIVgp120tg animals with IFNβ is sufficient to confer neuroprotection. Preliminary data from our lab describes the ability of HIVgp120 viral protein and IFNβ to regulate an important cell surface transmembrane ligand, ephrin-B1, in the CNS. Neuronal ephrin-B1 has been well studied and implicated in neuronal development, recruitment of NMDA receptors and synaptic plasticity mainly through its signaling with EphB receptors. However, ephrin-B1’s functional role in HIV, particularly microglial specific ephrin-B1, has not been well characterized at all. Our preliminary data identifies a statistically significant upregulation in EphB2 mRNA (one of the main receptors of ephrin-B1) in the cortex of HIV+ Patients with brain pathology. In addition, we describe significant inverse correlations between ephrin-B1 mRNA in the cortex of HIV+ Patients with both neurocognitive domain scores and inhibitory neuronal gene expression. In a transgenic NeuroHIV mouse in vivo model, we show in the cortex and hippocampus that the presence of gp120 upregulates ephrin-B1 protein expression in a cell-specific manner, including microglia. Treatment with IFNβ marginally reduces ephrin-B1 expression but significantly reduces ephrin-B1 off the surface of microglia. We believe that enhanced signaling between EphB2 and ephrin-B1 in the CNS of HIV+ Patients may lead to enhanced inflammatory response as well as unwanted synaptic pruning, and ablation of microglial ephrin-B1 will, in part, mitigate inflammation and synaptic pruning. This proposal seeks to identify the functional consequences of regulating microglial ephrin-B1 on microglial state and neuronal health in the context of HIV.