REPRESSION OF HIV-1 EXPRESSION IN THE LUNG

HIV-1在肺泡巨噬细胞(SAM)和淋巴细胞(AL)中的复制 被认为在临床潜伏期受到积极限制。随着疾病的发作 艾滋病和肺部感染的发展有增加的趋势 两者在肺中抑制HIV-1的数量尚未确定。 维生素A及其代谢衍生物(维甲酸)已被证明是 HIV-1在单核/巨噬细胞中表达的强大回归因子。肺脏 正常情况下含有大量的类维A酸，然而患有 艾滋病损害了他们维持维生素A动态平衡的能力 往往缺乏维生素A。CD8+淋巴细胞来源的水平 细胞因子、白介素16在HIV-1感染者的肺中也升高 人民。值得注意的是，IL-16治疗的CD4+T淋巴细胞抑制了 体外激活HIV-1 LTR定向表达。建议进行的实验 将决定维甲酸和IL-16是否能克服 通常在艾滋病患者的肺部发现的药物对HIV-1的激活 (肿瘤坏死因子-a、粒-巨噬细胞集落刺激因子、IL-1b、IL-6、结核分枝杆菌、肺孢子虫 卡氏杆菌、新生隐球菌)。更多的实验将确定 顺式作用于参与压制的DNA分子。的能力 将测量在AM中抑制HIV-1体外激活的维甲酸 作为疾病分期的函数。肺组织中类维甲酸和IL-16的状态 将被评估并与CD4+和CD8+T细胞水平和 疾病的发展。这些实验是长期目标的一部分 维甲酸和IL-16介导的分子机制研究 抑制和确定这些药物的治疗潜力。

HIV-1 replication in alveolar macrophages (SAM) and lymphocytes (AL) is thought to be actively restricted during clinical latency. With the onset of AIDS and the development of pulmonary infections there is an increase in both the number of HIV-1 repression in the lung have not been identified. Vitamin A and its metabolic derivatives (retinoids) have been shown to be potent regressors of HIV-1 expression in monocyte/macrophages. The lung normally contains significant levels of retinoids, however individuals with AIDS are compromised i their ability to maintain vitamin A homeostasis and are often vitamin A deficient. Levels of the CD8+ lymphocyte-derived cytokine, interleukin-16 are also elevated in the lungs of HIV-1 infected people. Significantly, IL-16 treatment of CD4+ T-lymphocytes represses the in vitro activation of HIV-1 LTR-directed expression. Experiments proposed in this application will determine whether retinoids and IL-16 can overcome HIV-1 activation by agents typically found i the lungs of AIDS patients (TNF-a, GM-CSF, IL-1b, IL-6, Mycobacterium tuberculosis, Pneumocystis carinii, Cryptococcus neoformans). Additional experiments will identify the cis=acting DNA elements involved in repression. The ability of retinoids to repress the ex vivo activation of HIV-1 in AM will be measured as a function of disease stage. The retinoid and IL-16 status of the lung will be evaluated and correlated with CD4+ and CD8+ T cell levels and disease progression. These experiments are part of the long term goal of both delineating he molecular mechanisms of retinoid and Il-16 mediated repression and determining the therapeutic potential of these agents.