ACTIVATION OF HIV-1 IN MACROPHAGES BY LUNG CELLS

描述（改编自申请人的摘要） 个人，特别是儿童，感染HIV-1是一个主要原因 发病率和死亡率。HIV-1感染的主要目标 肺内主要为T淋巴细胞和单核/巨噬细胞的CD 4细胞 血统病毒感染的CD 4淋巴细胞产生恒定的， 加速T细胞死亡，对T细胞磨损产生破坏性影响， 免疫功能相反，HIV-1感染组织巨噬细胞 不会立即导致细胞死亡，但可能会建立病毒 一个躲避宿主免疫系统的庇护所，一个新的 病毒可以被激活。拟议的长期目标 这项研究旨在阐明HIV-1激活的机制， 组织巨噬细胞这一假设是， 长末端重复序列中的转录调控元件 HIV-1基因组的序列调节细胞的激活和静止， 病毒通过与肺内皮细胞或成纤维细胞相互作用进入巨噬细胞 细胞建议研究的具体目标包括：（1） 比较HIV-1病毒LTR的功能和遗传特征 有或无肺部疾病表现的受感染儿童; (2)为了测量LTR的启动子功能的有效性， HIV-1感染儿童肺和外周血中的病毒 有或没有肺部疾病;和（3）鉴定LTR序列 参与介导HIV-1在细胞中的复制和激活 单核细胞/巨噬细胞谱系的体内足迹法， 区分5'和3' LTR的策略。拟议 跨学科的战略重点是肺组织中的病毒， 感染的儿童，实施新的体外培养方法， 巨噬细胞与肺源性内皮细胞和成纤维细胞，以及 整合来自临床和研究来源的数据。结果将 确定巨噬细胞和肺之间细胞接触的机制 内皮细胞或成纤维细胞调节LTR中的病毒因子， 介导病毒活化。

DESCRIPTION (Adapted from the Applicant's Abstract) Lung disease in individuals, especially children, with HIV-1 infection is a major cause of morbidity and mortality. The principal targets for HIV-1 infection in the lung are CD4 cells of T lymphocyte and monocyte/macrophage lineages. Virus infection of CD4 lymphocytes produces constant and accelerated T cell death with devastating impact on T cell attrition and immunologic function. In contrast, HIV-1 infection of tissue macrophages does not immediately produce cell death, but may establish for the virus a shelter from the host immune system and a reservoir from which new viruses can be activated. The long term objective of the proposed research is to elucidate mechanisms involved in activation of HIV-1 in tissue macrophages. The hypothesis is that natural genetic variation of transcriptional regulatory elements in the long terminal repeat (LTR) sequences of the HIV-1 genome modulate activation and quiescence of the virus in macrophages by interaction with lung endothelial or fibroblast cells. The specific aims of the proposed research include: (1) to compare functional and genetic characteristics of virus LTRs from HIV-1 infected children with and without manifestations of pulmonary disease; (2) to measure the effectiveness of the promoter function of LTRs from viruses in lung versus peripheral blood from HIV-1 infected children with or without pulmonary disease; and (3) to identify LTR sequences that participate in mediating HIV-1 replication and activation in cells of the monocyte/macrophage lineage by in vivo footprinting using a novel strategy to distinguish between the 5' and 3' LTRs. The proposed interdisciplinary strategy focuses on viruses within lung tissues of infected children, implements novel in vitro methods to culture macrophages with lung-derived endothelial and fibroblast cells, and integrates data from clinical and research sources. The results will identify mechanisms by which cell contact between macrophages and lung endothelial or fibroblast cells modulates virus factors in the LTR and mediates virus activation.