REPRESSION OF HIV-1 EXPRESSION IN THE LUNG

HIV-1在肺泡巨噬细胞（SAM）和淋巴细胞（AL）中的复制是 被认为在临床潜伏期期间被主动限制。 开始的时间 艾滋病和肺部感染的发展， 肺中HIV-1抑制的数量尚未确定。 维生素A及其代谢衍生物（类维生素A）已被证明是 单核细胞/巨噬细胞中HIV-1表达的有效消退因子。 肺 通常含有显着水平的类维生素A，然而， 艾滋病损害了他们维持维生素A体内平衡的能力， 往往缺乏维生素A。 CD 8+淋巴细胞源性 细胞因子，白细胞介素-16也在HIV-1感染者的肺中升高 人 值得注意的是，IL-16处理CD 4 + T淋巴细胞抑制了CD 4 + T淋巴细胞的增殖。 HIV-1 LTR定向表达的体外活化。 拟议的实验 将确定类维生素A和IL-16是否可以克服 艾滋病患者肺部常见的HIV-1激活剂 （TNF-α、GM-CSF、IL-1b、IL-6、结核分枝杆菌、肺孢子虫 卡氏隐球菌（Cryptococcus neoformans）。 其他实验将确定 参与阻遏的顺式作用DNA元件。 的能力 将测量类维生素A抑制AM中HIV-1的离体活化 作为疾病阶段的函数。 肺组织中维甲酸和IL-16的状态 将进行评估并与CD 4+和CD 8 + T细胞水平相关联， 疾病进展。 这些实验是长期目标的一部分， 这两种方法都揭示了维甲酸和IL-16介导的 抑制和确定这些药剂的治疗潜力。

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.