Studies of Cigarette Smoke Exposure in an Animal Model of HIV-1 Infection

描述（由申请人提供）：神经认知障碍（NCI），通常是艾滋病毒感染的一种毁灭性并发症，随着有效的抗逆转录病毒治疗的引入，感染者的生存时间延长，NCI正在上升。NCI发生的基础因素包括由于免疫细胞和神经胶质的增强活化而在这些个体的脑中释放神经毒性因子，释放细胞因子、趋化因子和其他可溶性感染介质。此外，HIV蛋白，特别是HIV糖蛋白和达特，已经被研究。 对神经元有直接毒性。在这项资助中，我们将开发一种模型， 研究吸烟（CS）暴露作为增加HIV感染者NCI风险的另一个潜在辅助因素的影响。我们的假设是，CS暴露可以通过诱导炎症反应和氧化应激反应在大脑中增加这种风险。我们还假设，这些反应可以覆盖尼古丁在抑制炎症和增强认知能力方面的潜在有益作用。据估计，超过40%的艾滋病毒阳性者是吸烟者，这一数字是普通人群中成人吸烟率估计值的两倍。CS中有超过4，000种化学物质和有毒物质，其中一些已被证明可能会因诱导炎症和氧化损伤而导致严重和永久的负面健康后果。吸烟已被证明会改变许多先天性和适应性免疫机制，并可引发可促进损伤的细胞氧化应激反应。在吸烟者中，CS导致白细胞增多，吸烟与较高的血浆HIV病毒载量和死亡率增加相关。尼古丁通过其成瘾特性促进吸烟。然而，在艾滋病毒感染者中，尼古丁可能会改善认知能力。尼古丁也被证明可以抑制免疫激活和促炎反应。因此，据推测，尼古丁或其代谢产物可用于治疗NCI。在以前的研究中，成年刘易斯大鼠，我们证明，CS暴露可导致显着的炎症和氧化应激反应，在暴露动物的大脑。因此，在拟定研究中，我们将检查CS中递送的尼古丁与单独尼古丁和含有最少量尼古丁的CS相比对HIV-1转基因大鼠模型中行为功能的影响。我们还将研究这种暴露对动物大脑中炎症和氧化应激产生的相对影响。这些研究应该提供线索的机制，可能有助于发生和发展的异常，已与发展和进展的NCI在HIV感染者。

DESCRIPTION (provided by applicant): Neurocognitive impairment (NCI), often a devastating complication of HIV infection, is on the rise as infected individuals survive longer with the introduction of effective antiretroviral therapy. Factors that underlie the occurrence of NCI include the release of neurotoxic factors in brains of such individuals as a result of enhanced activation of immune cells and glia, release of cytokines, chemokines and other soluble mediators of infection. In addition, HIV proteins, particularly HIV glycoprotein and tat, have been demonstrated to be directly toxic to neurons. In this grant we will develop a model that will allow for the examination of effects of cigarette smoke (CS) exposure as another potential co-factor in increasing the risk of NCI in HIV infected individuals. Our hypothesis is that CS exposure can increase such risk by inducing inflammation and oxidative stress response in brain. We also hypothesize that these responses can override potentially beneficial effects that have been demonstrated from nicotine in suppressing inflammation and enhancing cognitive abilities. It is estimated that over 40% of HIV+ individuals are cigarette smokers, a number that is twice the estimated prevalence of smoking among adults in the general population. There are greater than 4,000 chemicals and toxic substances in CS and a number have been shown to potentially cause serious and permanent negative health consequences due to the induction of inflammatory and oxidative damage. Cigarette smoking has been shown to alter a number of innate and adaptive immune mechanisms and can elicit cellular oxidative stress responses that can promote injury. In smokers, CS causes a leukocytosis and smoking is associated with higher plasma HIV viral loads and an increased mortality. Nicotine promotes cigarette smoking through its addictive properties. However, in individuals with HIV infection, nicotine may improve cognitive performance. Nicotine has been also shown to suppress immune activation and proinflammatory responses. Therefore, it has been speculated that nicotine or its metabolites may be useful for treating NCI. In previous studies in adult Lewis rats, we demonstrated that CS exposure can result in marked inflammatory and oxidative stress responses in the brains of the exposed animals. Therefore, in the proposed studies we will examine the effects of nicotine delivered in CS on behavioral function in the HIV-1 transgenic rat model as compare to nicotine alone and to CS that contains minimal amounts of nicotine. We will also examine the relative effects of such exposures on the generation of inflammation and oxidative stress in the brains of the animals. These studies should provide clues regarding mechanisms that might contribute to the occurrence and progression of abnormalities that have been linked to the development and progression of NCI in HIV infected individuals.