Nicotinic Acid Receptor Activation and Brain Proinflammatory Responses in HIV-1 Transgenic Rat

神经系统并发症通常发生在艾滋病毒感染中，超过40%的人面临 发生HIV相关神经认知障碍(NCI)，有效时代人数增加 抗逆转录病毒治疗(1)。NCI发生的基础因素包括由于 促进促炎细胞因子(如肿瘤坏死因子-α和白介素1-β)和其他炎症介质的产生 它们是由大脑中感染艾滋病毒的细胞分泌的(2，3)。造成这种反应的原因是减损。 正常线粒体所必需的烟酰胺腺嘌呤二核苷酸(NAD)介导的代谢 细胞中能量底物的功能和产生。在这笔赠款中，我们将分析以下潜在影响 暴露于香烟烟雾(CS)和尼古丁是增加HIV感染者NCI风险的共同因素 个人。吸烟已被证明改变了许多先天和适应性免疫机制。 并可引发细胞氧化应激反应，从而促进损伤。市场上最畅销的香烟品牌 含有不同量的尼古丁。在吸烟者中，CS会导致白细胞增多，在艾滋病毒感染者中， 吸烟与更高的血浆HIV病毒载量和更高的死亡率有关。据估计， 超过40%的艾滋病毒携带者是吸烟者(6)，这个数字是估计流行率的两倍 在一般人群中的成年人吸烟(7)。尼古丁，通过激活烟碱型乙酰胆碱受体 (NAChR)，通过其令人上瘾的特性促进吸烟。通过激活这些受体，尼古丁 也被证明通过直接影响免疫激活和促炎反应 免疫细胞以及通过激活尼古丁受体介导的途径(8-10)。 然而，由于HIV蛋白的影响以及长期尼古丁暴露和nAChR上调， 已观察到促炎反应增加，从而可能导致中枢神经系统损伤 这发生在艾滋病毒感染的背景下。在先前对成年Lewis大鼠的研究中，我们证明了CS 暴露可导致暴露者大脑中显著的炎症和氧化应激反应 动物(11)。我们随后证明，这种效应也可以在HIV-1转基因中观察到。 与相应的野生型动物相比，老鼠的反应更显著。 我们还提供了证据表明，这种反应可以由CS中存在的尼古丁驱动。激活 NAChR还可以调节细胞内NAD的水平和相关代谢途径的激活。潜力 这种激活在HIV感染和脑内慢性炎症发生中的作用尚未得到证实 以前研究过的。拟议的研究将利用转基因大鼠模型在体内进行，以及 在体外，利用原代星形胶质细胞培养，表达与体内转基因大鼠相同的HIV基因。

Neurological complications occur commonly in HIV infection, with over 40% of individuals being at risk for developing HIV-related neurocognitive impairment (NCI), with the numbers increasing in the era of effective antiretroviral therapy (1). Factors that underlie the development of NCI include neuronal dysfunction due to enhanced production of proinflammatory cytokines (e.g., TNF-α and IL-1β) and other inflammatory mediators that are secreted by HIV-infected cells in the brain (2,3). Contributing to such responses is impairment metabolism mediated by nicotinamide adenine dinucleotide (NAD), which is essential for normal mitochondrial function and the production of energy substrates in cells. In this grant, we will analyze potential effects of exposure to cigarette smoke (CS) and nicotine as co-factors for increasing the risk of NCI in HIV infected individuals. 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. Most marketed brands of cigarettes contain varying amounts of nicotine. In smokers, CS causes a leukocytosis and, in HIV-infected individuals, smoking is associated with higher plasma HIV viral loads and an increased mortality. It has been estimated that over 40% of HIV+ individuals are cigarette smokers (6), a number that is twice the estimated prevalence of smoking among adults in the general population (7). Nicotine, via activation of nicotinic acetylcholine receptors (nAChR), promotes cigarette smoking through its addictive properties. By activating these receptors, nicotine has been also shown to suppress immune activation and proinflammatory responses through direct effects on immune cells as well as through pathways that are mediated by activation of nicotine receptors (8-10). However, due to effects of HIV protein and with chronic nicotine exposure and upregulation of nAChR, proinflammatory responses have been observed to increase, thereby potentially contributing to CNS damage that occurs in the context of HIV infection. 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 (11). We have subsequently demonstrated that such effects can be also observed in HIV-1 transgenic rats, with more prominent responses developing than what are observed in corresponding wild-type animals. We also provide evidence that such responses can be driven by nicotine that is present in the CS. Activation of nAChR can also regulate cellular levels of NAD and activation of associated metabolic pathways. The potential effects of such activation in HIV infection and the generation of chronic inflammation in brain has not been previously studied. The proposed studies will be performed in vivo utilizing the transgenic rat model as well as in vitro utilizing primary astrocyte cultures that express the same HIV genes as the transgenic rat in vivo.