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，随着引入有效的抗逆转录病毒治疗，感染者的生存时间延长，神经认知障碍（NCI）正在上升。NCI发生的潜在因素包括，由于免疫细胞和神经胶质细胞的激活增强，这些个体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性感染介质。此外，HIV蛋白，特别是HIV糖蛋白和tat，已经被研究

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.