HIV TAT EFFECT ON ENDOTHELIAL CELL FUNCTION

感染人类免疫缺陷病毒1（HIV）的患者是 与内皮功能的不同改变有关。这些 包括以不适当内皮细胞（EC）为标志的综合征 增生（原发性肺动脉高压），分化不全 （卡波西肉瘤）和急性炎症（肺炎，心肌炎， 脑炎、心包炎）。 虽然这些扰动在欧共体 功能可以是弥漫性的，HIV直接感染EC是不常见的，可能 仅限于某些脉管床，并且通常是流产的。 等 因此，内皮细胞的改变更有可能是 HIV相关的循环介质，而不是直接的内皮 逆转录病毒感染。 我们假设分泌的HIV转录因子达特作用于 调节EC增殖、分化、凋亡和表达 炎症分子，此外，这些影响是 由细胞因子TNF α、IL-1 β和IFN γ调节。 我们 进一步假设，不同的，有时相反的影响， 达特是由氧化剂依赖的差异激活介导的， 各种MAP激酶信号传导盒。 我们的初步数据证实，人体EC暴露于达特急性 增加细胞内氧化剂水平，同时激活 c-Jun氨基末端激酶（JNK）。 此外，达特改变了TNF-α- 介导的JNK激活和JNK的DNA结合亲和力。 转录因子AP-1是JNK的潜在靶点。 我们的总体目标是关联氧化酶组装，氧化剂 产生、MAPK激活、DNA结合和启动子激活 转录因子，与细胞表型（增殖， 分化、凋亡、炎性分子表达，以及 白细胞粘附）在暴露于达特和细胞因子的人EC中，使用 各种干预措施旨在剖析不同的信号 途径。 这项工作的意义在于进一步深入了解 各种艾滋病相关血管综合征的原因，以及 了解正常人基本EC功能的基础。 这可能会导致对艾滋病毒感染者的特定治疗， 还提出了治疗非HIV相关疾病的新策略 通过调节内皮细胞功能。

Infection of patients with Human Immunodeficiency Virus 1 (HIV) is associated with diverse alterations in endothelial function. These include syndromes marked by inappropriate endothelial cell (EC hyperplasia (primary pulmonary hypertension), incomplete differentiation (Kaposi's sarcoma), and acute inflammation (pneumonitis, myocarditis, encephalitis, pericarditis). Although these perturbations in EC function can be diffuse, direct infection of EC by HIV is unusual, may be restricted to certain vascular beds, and is generally abortive. Such endothelial alterations are therefore more likely to be the result of HIV-related circulating mediators, rather than of direct endothelial infection by retrovirus. We hypothesize that the secreted HIV transcription factor Tat acts to modify EC proliferation, differentiation, apoptosis, and expression of inflammatory molecules, and additionally, that these effects are modulated by the cytokines TNF alpha, IL-1 beta, and IFN gamma. We further hypothesize that the diverse and sometimes opposing effects of Tat are mediated by the oxidant-dependent differential activation of the various MAP Kinase signaling cassettes. Our preliminary data confirm that exposure of human EC to Tat acutely increases intracellular oxidant levels concomitant with activation of c-Jun amino terminal kinase (JNK). Further, Tat alters the TNF-alpha- mediated activation of JNK and the DNA-binding affinity of the transcription factor AP-1, a potential target of JNK. Our general objectives are to correlate oxidase assembly, oxidant production, MAPK activation, and DNA binding and promoter activation of transcription factors, with cell phenotype (proliferation, differentiation, apoptosis, inflammatory molecule expression, and leukocyte adhesion) in human EC exposed to Tat and cytokines, using a variety of interventions designed to dissect different signaling pathways. The significance of this work is to provide further insight into the cause of various AIDS-related vascular syndromes, as well as to understand the basis for fundamental EC functions in normal individuals. This may lead to specific treatments for HIV-infected patients, and may also suggest novel strategies for treatment of non-HIV related diseases through modulation of endothelial cell function.