LYMPHOCYTE ADHESION AND HIV ACTIVATION IN THE LUNG

艾滋病毒感染的肺部表现包括机会性 感染以及与原发性艾滋病毒感染有关的并发症， 例如间质性肺炎。间质的发展 肺炎需要靶向淋巴细胞和其他炎症 细胞粘附和迁移到肺， 内皮屏障淋巴细胞的粘附和迁移是 通过整合素（一类细胞粘附分子）介导。我们 提出HIV感染的淋巴细胞改变了 整合素的功能。这一假设得到了初步数据的支持 表明纤连蛋白受体α 5 β 1 HIV感染的H9淋巴细胞。整合素表达的改变可能导致 肺内淋巴细胞的不适当积聚 导致肺炎的发生。我们假设 淋巴细胞粘附本身导致HIV基因的上调 表情这种机制可以提供一种潜在的途径， 感染细胞在肺内的永久存在。也有可能 其它刺激可与粘附协同作用， 病毒复制 我们建议研究HIV感染对淋巴细胞的影响， 整合素 这将通过检查表面表达来完成 整合素在慢性感染淋巴细胞上的粘附功能 和急性感染的初级淋巴细胞。我们还将确定 单个HIV基因产物（包括达特）对整合素的影响 表情淋巴细胞粘附在肺内HIV活化中的作用 也将被审查。这将通过检查 粘附于肺微血管内皮细胞和基质 肺中重要的蛋白质。我们将确定p24抗原水平， 病毒基因表达的指标。粘附力影响 将通过检查转染有 荧光素酶报告基因上游的HIV LTR启动子。 这项建议旨在增加我们对 HIV感染淋巴细胞与肺微血管的相互作用 内皮细胞这可能最终导致治疗干预 旨在影响淋巴细胞粘附。

Pulmonary manifestations of HIV infection include both opportunistic infections as well as complications related to primary HIV infection, such as interstitial pneumonitis. The development of interstitial pneumonitis requires targeting of lymphocytes and other inflammatory cells to the lung followed by the adhesion and migration of cells through the endothelial barrier. Adhesion and migration of lymphocytes are mediated through integrins, a class of cell adhesion molecules. We propose that HIV infection of lymphocytes alters the expression and function of integrins. This hypothesis is supported by preliminary data indicating increased expression of the fibronectin receptor, alpha5Beta1 on HIV-infected H9 lymphocytes. Altered expression of integrins may lead to inappropriate accumulation of lymphocytes in the pulmonary interstitium, leading to the development of pneumonitis. We hypothesize that lymphocyte adhesion itself results in upregulation of HIV gene expression. This mechanism may provide a potential route to allow the perpetuation of infected cells within the lung. It is also possible that other stimuli may act in synergy with adhesion and result in increased viral replication. We propose to investigate the effect of HIV infection on lymphocyte integrins. This will be accomplished by examining the surface expression and adhesive function of integrins on chronically infected lymphocytes and acutely infected, primary lymphocytes. We will also determine the effect of individual HIV gene products, including Tat, on integrin expression. The role of lymphocyte adhesion on HIV activation in the lung will also be examined. This will be accomplished by examining the effects of adhesion to pulmonary microvascular endothelial cells and matrix proteins important in the lung. We will determine p24 antigen levels as an indicator of viral gene expression. The ability of adhesion to affect transcription will be tested by examining Jurkat cells transfected with HIV LTR promoter upstream from the luciferase reporter gene. This proposal is designed to increase our understanding of the interactions between HIV-infected lymphocytes and pulmonary microvascular endothelium. This may eventually lead to therapeutic interventions designed to impact on lymphocyte adhesion.