HIV TAT EFFECT ON ENDOTHELIAL CELL FUNCTION

人类免疫缺陷病毒1型(HIV)患者的感染情况 与内皮功能的不同变化有关。这些 包括以不适当内皮细胞(EC)为标志的症状 增生(原发性肺动脉高压)，分化不全 (卡波西氏肉瘤)和急性炎症(肺炎、心肌炎、 脑炎、心包炎)。尽管欧共体中的这些扰动 功能可扩散，由HIV直接感染EC是不寻常的，可能 仅限于某些血管床，通常是流产的。是这样的 因此，内皮细胞的改变更有可能是 HIV相关循环介质，而不是直接内皮细胞 被逆转录病毒感染。 我们假设分泌的HIV转录因子Tat作用于 改变EC增殖、分化、凋亡及相关基因的表达 炎症分子，此外，这些影响是 受细胞因子肿瘤坏死因子α、白介素1β和干扰素γ的调节。我们 进一步的假设是，不同的，有时是相反的影响 TAT是由氧化剂依赖的差异激活的 不同的MAP激活酶信号盒。 我们的初步数据证实了人类EC对TAT的暴露 伴随着细胞内氧化剂水平的增加而激活 C-jun氨基末端激酶(JNK)。此外，TAT还改变了肿瘤坏死因子-α- JNK的介导激活及其与DNA的亲和力 转录因子AP-1，JNK的潜在靶点。 我们的总体目标是将氧化酶组装、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 在暴露于TAT和细胞因子的人EC中，使用一种 旨在剖析不同信号的各种干预措施 小路。 这项工作的意义在于提供了对 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。 这可能导致对艾滋病毒感染患者的特定治疗，并可能 还提出了治疗非艾滋病毒相关疾病的新策略 通过对内皮细胞功能的调节。

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.