LYMPHOCYTE ADHESION AND HIV ACTIVATION IN THE LUNG

HIV感染的肺部表现包括机会性 感染以及与原发艾滋病毒感染有关的并发症， 比如间质性肺炎。间隙组织的发展 肺炎需要靶向淋巴细胞和其他炎症性细胞 细胞进入肺后的黏附和迁移 内皮屏障。淋巴细胞的黏附和迁移是 通过整合素介导，这是一类细胞黏附分子。我们 认为HIV感染淋巴细胞改变了其表达和 整合素的功能。这一假设得到了初步数据的支持 表明纤维连接蛋白受体α5β1的表达增加 在感染艾滋病毒的H9淋巴细胞上。整合素表达的改变可能会导致 由于淋巴细胞在肺内的不适当聚集 间质，导致肺炎的发展。我们假设 淋巴细胞黏附本身导致HIV基因上调 表情。这一机制可以提供一条潜在的路线，以允许 肺内感染细胞的永久化。也有可能是 其他刺激可能与粘连协同作用，并导致增加 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式来实现 整合素在慢性感染淋巴细胞上的黏附功能 以及受到急性感染的初级淋巴细胞。我们还将确定 包括TAT在内的单个HIV基因产物对整合素的影响 表情。淋巴细胞黏附在肺内HIV激活中的作用 还将接受检查。这将通过检查影响来实现 与肺微血管内皮细胞和基质的黏附 对肺部很重要的蛋白质。我们将测定p24抗原水平为 病毒基因表达的指标。粘附力影响的能力 将通过检测转基因Jurkat细胞来测试转录 HIV LTR启动子位于荧光素酶报告基因的上游。 这项建议旨在增加我们对 HIV感染的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。 旨在影响淋巴细胞黏附。

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.