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3700万人被诊断出感染了人类免疫缺陷病毒(HIV)。在这3700万人中， 据估计，15%-55%的艾滋病毒携带者患有艾滋病毒相关的神经认知障碍(HAND)。上一首 我们和其他实验室的工作发现，β干扰素(干扰素β)和抗病毒1型干扰素的短暂增加， 在HIVgp120转基因小鼠和SIV模型中出现任何行为或神经病理症状之前， 提示干扰素β在早期艾滋病毒感染中具有神经保护作用。我们之前已经证明了外生的 HIVgp120tg动物鼻腔内暴露干扰素β足以提供神经保护。初步数据 来自我们实验室的研究人员描述了HIVgp120病毒蛋白和干扰素β调节重要细胞表面的能力 中枢神经系统中的跨膜配体--eaffin-B1。神经元型eaffin-B1已经被很好地研究并与 神经元发育、NMDA受体募集和突触可塑性主要通过其信号转导途径来实现 EphB受体。然而，S在艾滋病病毒中的功能作用，特别是小胶质细胞特异性的ephin-B1，并没有 被很好地刻画出来了。 我们的初步数据表明，EphB2 mRNA(主要受体之一)在统计学上有显著上调 在有脑病理的HIV阳性患者的大脑皮质中)。此外，我们还描述了显著逆 HIV+患者大脑皮层ephin-B1mRNA与神经认知领域评分的相关性 和抑制神经元基因的表达。在体内的转基因神经艾滋病毒小鼠模型中，我们在皮质中显示 和海马区，gp120的存在以细胞特异性的方式上调eaffin-B1蛋白的表达， 包括小胶质细胞。干扰素β治疗略微减少ePhin-B1的表达，但显著减少 小胶质细胞表面的E蛋白-B_1。我们认为EphB2和ePhin-B1之间的信号增强在 HIV+患者的中枢神经系统可能导致炎症反应增强以及不必要的突触修剪，以及 消融小胶质细胞eparin-B1将在一定程度上减轻炎症和突触修剪。这项建议旨在 确定调节小胶质细胞ephin-B1对小胶质细胞状态和神经元健康的功能影响 在艾滋病毒的背景下。

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.