Methamphetamine, Brain Endothelial TLR3 Signaling and HIV

描述（由申请人提供）：甲基苯丙胺（冰毒）滥用和人类免疫缺陷病毒（HIV）感染在美国产生了“双重流行病”，这是一个严重的全球公共卫生问题。冰毒滥用和艾滋病毒感染都被认为是神经认知疾病的主要原因。在艾滋病毒感染的情况下，使用冰毒会增加感染艾滋病毒的风险，并增加脑损伤。然而，甲基苯丙胺和/或HIV损害中枢神经系统（CNS）的机制尚不清楚。人脑微血管内皮细胞（HBMEC）是血脑屏障（BBB）的主要组成部分，在保护中枢神经系统免受病原体侵袭方面发挥着关键作用。最近，我们发现HBMEC是抑制HIV在巨噬细胞中复制的重要旁观者，因为HBMEC的toll样受体3 （TLR3）信号传导可以激活IFN途径，诱导细胞内HIV限制因子的表达。在拟议的研究中，我们将确定甲基安非他明和/或HIV是否会损害TLR3信号介导的HBMEC免疫激活和HBMEC介导的抗HIV活性。该R03提案的总体假设是甲基安非他明和/或HIV损害HBMEC的TLR3信号，降低HBMEC介导的抗HIV先天免疫。我们提出了两个具体目标：1)确定甲基安非他明和/或HIV对hbmec介导的抗HIV活性的TLR3信号的影响；2)研究甲基安非他明和/或HIV在HBMEC TLR3信号通路下对血脑屏障通透性的影响，以及HBMEC TLR3信号通路是否对甲基安非他明和/或HIV介导的神经元损伤具有保护作用。鉴于甲基苯丙胺使用的高流行率及其对HIV相关痴呆的影响，提出的研究是及时和重要的，它应该提供在甲基苯丙胺使用和/或HIV感染背景下HBMEC在血脑屏障先天免疫中的作用。

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse and human immunodeficiency virus (HIV) infection produce a "double epidemic" in the United States, which is a serious global concern to public health. METH abuse and HIV infection are both recognized as major causes of neurocognitive diseases. METH use can increase the risk of acquiring HIV and enhance brain injury in the context of HIV infection. However, it is unclear about the mechanisms by which METH and/or HIV impair the central nervous system (CNS). Human brain microvascular endothelial cells (HBMEC) have been well known as main components of the blood-brain barrier (BBB) and play a key role in protecting the CNS from pathogen invasion. Recently, we identified HBMEC as an important bystander in inhibiting HIV replication in macrophages, as Toll-like receptor 3 (TLR3) signaling of HBMEC could activate IFN pathway, inducing the expression of the cellular HIV restriction factors. In the proposed studies, we will determine whether METH and/or HIV compromise TLR3 signaling-mediated immune activation of HBMEC and HBMEC-mediated anti-HIV activity. The overarching hypothesis of this R03 proposal is that METH and/or HIV impair TLR3 signaling of HBMEC, diminishing HBMEC-mediated innate immunity against HIV. We propose two specific aims: 1) to determine the effect of METH and/or HIV on TLR3 signaling of HBMEC-mediated anti-HIV activity; 2) to examine the impact of METH and/or HIV on BBB permeability in the context of TLR3 signaling of HBMEC, and whether TLR3 signaling of HBMEC has protective effect on METH and/or HIV-mediated neuronal injury. Given the high prevalence of METH use and its implication in HIV-associated dementia, the proposed studies are timely and important, which should provide insight of the role of HBMEC in BBB innate immunity in the context of METH use and/or HIV infection.