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

描述(申请人提供)：神经认知障碍(NCI)，通常是艾滋病毒感染的破坏性并发症，随着有效的抗逆转录病毒治疗的引入，感染者的存活时间更长，这种情况正在增加。NCI的发生因素包括由于免疫细胞和神经胶质细胞的激活而在这些人的大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的感染媒介。此外，艾滋病毒蛋白，特别是艾滋病毒糖蛋白和Tat，已经被 证明对神经元有直接毒性。在这笔赠款中，我们将开发一种模型，将允许 检查暴露于香烟烟雾(CS)的影响，这是增加艾滋病毒感染者非传染性疾病风险的另一个潜在辅助因素。我们的假设是，CS暴露可以通过在大脑中诱导炎症和氧化应激反应来增加这种风险。我们还假设，这些反应可以盖过尼古丁在抑制炎症和增强认知能力方面的潜在有益影响。据估计，超过40%的艾滋病毒携带者是吸烟者，这一数字是一般人口中成年人吸烟估计流行率的两倍。CS中含有4,000多种化学物质和有毒物质，其中一些已被证明可能由于引起炎症和氧化损害而造成严重和永久性的负面健康后果。吸烟已被证明可以改变一些先天和适应性免疫机制，并可以引发细胞氧化应激反应，从而促进损伤。在吸烟者中，CS导致白细胞增多，吸烟与较高的血浆HIV病毒载量和增加的死亡率相关。尼古丁通过其令人上瘾的特性促进吸烟。然而，在感染艾滋病毒的人中，尼古丁可能会改善认知能力。尼古丁还被证明可以抑制免疫激活和促炎反应。因此，有人推测尼古丁或其代谢产物可能对治疗NCI有用。在先前对成年Lewis大鼠的研究中，我们证明CS暴露可导致暴露动物大脑中显著的炎症和氧化应激反应。因此，在拟议的研究中，我们将检查CS中传递的尼古丁对HIV-1转基因大鼠模型中行为功能的影响，并与单独使用尼古丁和含有最低尼古丁的CS进行比较。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。这些研究应该提供关于可能导致异常发生和进展的机制的线索，这些异常与艾滋病毒感染者的NCI的发展和进展有关。

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.