Opioid- and HIV-mediated effects on the integrity of the blood-brain barrier, on immune cell recruitment, and on antiretroviral penetration into the brain

尽管积极使用联合抗逆转录病毒疗法，但艾滋病毒感染与认知和 神经行为障碍，统称为神经艾滋病毒。艾滋病毒和鸦片类药物与 血脑屏障(BBB)功能障碍、炎症信号改变以及认知和运动障碍。 HIV病毒蛋白Tat被认为是大脑中与HIV相关的大部分损害的媒介。这 该提案将同时使用TAT转基因小鼠模型和小鼠嗜性HIV感染小鼠模型。纹身 转基因小鼠模型在GFAP启动子的驱动下表达HIV-1Tat，这将表达限制在CNS。 这两个模型将被用来检验艾滋病毒和吗啡在体内的影响。我们的中心假设是 阿片类药物通过复杂的机制损害血脑屏障功能并促进神经病理 包括增加细胞旁的通量，同时矛盾地减少跨越屏障的抗逆转录病毒药物的净通量， 增加单核细胞的渗透，增加大脑内的炎症信号。我们将解决我们的 有以下具体目的的假设。目的1.确定阿片类药物±HIV-1 TAT和HIV感染的影响 血脑屏障的完整性和功能以及对抗逆转录病毒药物和吗啡浓度的区域特异性影响 在大脑里。目的2.表征鸦片类药物±HIV/HIV-1 TAT和TAT之间相互作用的地区差异 ARV对巨噬细胞向中枢神经系统的渗透和中枢神经系统促炎细胞因子的产生的影响。这些 研究将确定和联系阿片剂和/或艾滋病毒-1对区域药物积累、血脑屏障完整性、 药物代谢/外流，以及免疫细胞进入大脑和大脑内的炎症信号。更好 对这种动态相互作用的理解，特别是对抗逆转录病毒脑浓度的关注，将会改善 目前对使用阿片类药物(合法或非法使用)的艾滋病毒患者的治疗方法。 长期目标是了解阿片类药物如何限制脑内ARV的治疗效果 并确定治疗发展的目标，以消除阿片剂/艾滋病毒对 神经认知结果。

Despite aggressive use of combination antiretroviral therapy, HIV infection is associated with cognitive and neurobehavioral impairment, collectively termed neuroHIV. HIV and opiates are independently associated with blood brain barrier (BBB) dysfunction, alterations in inflammatory signaling, and cognitive and motor deficits. The HIV viral protein Tat is thought to mediate much of the HIV-associated damage within the brain. This proposal will use both a Tat transgenic mouse model and a murine tropic HIV-infected mouse model. The Tat transgenic mouse model expresses HIV-1 Tat driven by a GFAP promotor, which limits expression to the CNS. The two models will be used to examine the effects of HIV and morphine in vivo. Our central hypothesis is that opiates compromise BBB function and contribute to neuropathology through complex mechanisms which include enhancing paracellular flux, while paradoxically decreasing net flux of antiretrovirals across the barrier, increasing infiltration of monocytes, and increasing inflammatory signals within the brain. We will address our hypotheses with the following specific aims. Aim 1. Define the effects of opiates ± HIV-1 Tat and HIV infection on BBB integrity and function and on region-specific impact on antiretrovirals and morphine concentrations within the brain. Aim 2. Characterize regional differences in the interplay between opiates ± HIV/HIV-1 Tat and ARVs on macrophage infiltration into the CNS and on proinflammatory cytokine production the CNS. These studies will define and relate the effects of opiates and/or HIV-1 on regional drug accumulation, BBB integrity, drug metabolism/efflux, and immune cell trafficking into and inflammatory signals within the brain. Better understanding of this dynamic interplay, with specific focus on antiretroviral brain concentrations, will improve the current therapeutic approaches for the HIV patients who use opioids (for licit or illicit use). The long-term goal is to understand how opiates limit ARV therapeutic efficacy within the brain in the setting of HIV and to identify targets for therapeutic development to eliminate the negative effects of opiates/HIV on neurocognitive outcomes.