Cross-species studies of smoking effects on cognition and neuroinflammation in HIV

摘要 HIV-1感染者吸烟率（40%）高于普通人群（16%），非HIV感染者吸烟率（40%）高于普通人群（16%）。 吸烟者戒烟的能力更强。鉴于艾滋病毒感染从“致命”转为“慢性”， 吸烟率的增加可能会对长期健康结果产生负面影响。了解为什么利率 仍然是帮助戒烟的关键鉴于艾滋病毒感染会导致炎症， 尼古丁（烟草的主要精神活性成分）可以减少炎症，艾滋病毒感染者可以吸烟， 一种消除症状的方法。尼古丁具有多种作用，包括改善认知领域 这些基因是艾滋病病毒携带者缺乏的。另外，艾滋病毒感染者可能会继续吸烟，因为他们 比一般人群经历更大的戒断效应。本项目将研究这些潜力 机制等目标1将确定目前吸烟对认知功能的影响，并使用正电子 放射断层扫描（PET）标记物，以确定HIV阳性和健康参与者的神经炎症 （n=21/gp）。反向转换任务和NIH工具包将描述以下方面的潜在积极益处： 艾滋病毒阳性参与者的吸烟饱腹感。此外，目前基于小胶质细胞的神经炎症标记物将 并与认知表现进行比较。虽然信息量很大，但这种横向分析不会 能够确定影响的方向性。因此，目标2将确定慢性尼古丁的方向性， 戒断对表达HIV相关gp 120蛋白的小鼠的认知和神经炎症的影响 和它们的野生型（WT）同窝仔。在Expt. 1，慢性尼古丁对认知的影响将被检查 使用Aim 1中的啮齿动物任务。此外，类似的神经炎症标志物将在 每个治疗阶段（基线、急性、慢性和停药诱导效应）。在Expt. 2、这项工作将 在HIV的gp 120-小鼠模型中重复，以确定尼古丁与这种HIV的潜在相互作用- 相关蛋白质最后，Expt。3将包括抗逆转录病毒治疗（ART;整合酶抑制剂），以确定 尼古丁，gp 120蛋白和ART对认知和神经炎症的潜在三向相互作用。 因此，协同增强（在尼古丁治疗期间）和缺陷（在尼古丁治疗期间）的可能性是显著的。 将确定每个因素的影响。最后，多巴胺和烟碱受体的潜在变化 将检查表达。因此，这些研究将建立与艾滋病毒相关的认知缺陷的概况 和吸烟/尼古丁共病，以及它们与神经炎症的联系。更重要的是，使用cross- 物种相关的测试，“鸡还是蛋”的难题将得到回答， 吸烟更多，戒烟更困难，因为尼古丁对这种缺陷有特殊的补救作用 和/或更大的有害作用。神经病理学研究也将有助于确定 治疗开发和戒烟的潜在目标有助于改善艾滋病毒患者的生活。

ABSTRACT People with HIV-1 infection smoke at higher rates (40%) than the general population (16%), with non-HIV smokers showing a greater ability to quit. Given the movement of HIV infection from a `fatal' to `chronic' disease, increased smoking rates may negatively impact long-term health outcomes. Understanding why rates are so high remains critical to aiding quit attempts. Given that HIV infection results in inflammation, and nicotine (the primary psychoactive ingredient of tobacco) reduces inflammation, people with HIV may smoke as a means to medicate symptoms. Nicotine exerts numerous effects including improvement in cognitive domains that are deficient in people with HIV. Alternatively, those with HIV may continue to smoke because they experience greater withdrawal effects than the general population. This project will investigate these potential mechanisms. Aim 1 will determine the impact of current smoking on cognitive functioning and use a positron emission tomography (PET) marker to determine neuroinflammation in HIV positive and healthy participants (n=21/gp). Reverse-translated tasks and the NIH Toolkit will characterize the potential positive benefits of smoking satiety in HIV positive participants. Further, current microglia-based neuroinflammatory markers will be determined and compared to cognitive performance. While informative, this cross-sectional analysis will not be able to determine directionality of effects. Hence, Aim 2 will determine directionality of chronic nicotine & withdrawal effects on cognition and neuroinflammation in mice that express the HIV-associated gp120 protein and their wildtype (WT) littermates. In Expt. 1, the effects of chronic nicotine on cognition will be examined using rodent-based tasks from Aim 1. In addition, similar neuroinflammatory markers will be investigated at each stage of treatment (baseline-, acute-, chronic-, and withdrawal-induced effects). In Expt. 2, this work will be repeated in the gp120-mouse model of HIV to determine nicotine's potential interactive effects with this HIV- relevant protein. Finally, Expt. 3 will include antiretroviral treatment (ART; an integrase inhibitor) to determine potential three-way interactions of nicotine, gp120 protein, and ART on cognition and neuroinflammation. Hence, the potential for synergistic enhancement (during nicotine treatment) and deficits (during nicotine withdrawal) on each factor will be determined. Finally, potential changes in dopamine and nicotinic receptor expression will be examined. Hence, these studies will establish the cognitive profile of deficits related to HIV and comorbid cigarette/nicotine use, as well as their link to neuroinflammation. More importantly, using cross- species relevant testing, the `chicken or the egg' conundrum will be answered as to whether those with HIV smoke more and have greater difficulty quitting because of a specific remediation of such deficits with nicotine and/or greater deleterious effects during withdrawal respectively. Neuropathology studies will also help identify potential targets for treatment development and smoking cessation aids to improve the lives of HIV sufferers.