HIV-Nef protein and endothelial dysfunction

 描述(申请人提供)：抗病毒治疗在预防艾滋病毒感染者艾滋病方面是有效的。然而，越来越多的艾滋病毒感染者遭受甚至死于艾滋病以外的疾病，包括心血管疾病。这些临床观察背后的生物学机制尚不清楚，尽管抗逆转录病毒疗法(ART)依赖和独立的机制似乎都参与了这一过程。在这里，我们计划研究HIV可导致内皮细胞激活和功能障碍的关键机制，这被认为是动脉粥样硬化过程的先导。已知NEF在HIV的发病机制中发挥关键作用，并介导其自身从T细胞向旁观者细胞的转移。因此，我们推测HIV-Nef可以有效地从T细胞转移到包括血管内皮细胞在内的其他血细胞 细胞，这些细胞与流动的血液和淋巴液体稳定接触。事实上，我们可以证明Nef的转移导致内皮细胞激活和细胞死亡，这可以被NADPH氧化酶抑制剂和抗氧化剂有效地消除。根据我们已发表的数据，可以通过将Nef从血细胞转移到冠状动脉内皮细胞来解释HIV依赖的内皮激活，我们进一步假设Nef转移到血管细胞可能导致心血管功能障碍和心血管系统的病理。我们计划在临床前的体外和体内模型中探讨Nef转移到Nef的机制和Nef在 内皮细胞。我们预计，确定这样的靶点将使临床干预研究能够使用适当的抑制剂。因此，确定Nef诱导血管内皮细胞病变的细胞机制有助于确定HIV-Nef是预防和治疗HIV相关疾病的新靶点。

 DESCRIPTION (provided by applicant): Antiviral therapy is effective in preventing AIDS in HIV-infected people. However, an increasing number of HIV infected individuals suffer or even die of diseases other than AIDS including cardiovascular diseases. The biology behind these clinical observations is not well understood, although both anti-retroviral therapy (ART) dependent and independent mechanisms appear to be involved. Here we plan to study a key mechanism by which HIV can cause endothelial activation and dysfunction, which are believed to precede atherosclerotic processes. Nef is known to play a pivotal role in HIV pathogenesis and to mediate its own transfer from T cells to bystander cells. Therefore, we postulate that HIV-Nef can efficiently be transferred from T cells to other blood cells including vascular endothelial cells, which are in steady contact with flowing blood and lymph fluid. Indeed, we can show that transfer of Nef leads to endothelial cell activation and cell death, which can be effectively abrogated by NADPH oxidase inhibitors and antioxidants. Based on our published data that HIV dependent endothelial activation can be explained by transfer of Nef from blood cells to coronary arterial endothelial cells, we further hypothesize that transfer of Nef to vascular cells may lead to cardiovascular dysfunction and pathology of the cardiovascular system. We plan to address in preclinical in vitro and in vivo models the mechanism of Nef transfer to and activity in endothelial cells. We expect that identifying such targets will enable clinical interventions studis with appropriate inhibitors. Thus, determining the cellular mechanism of Nef-induced vascular pathology in vascular endothelial cells can help to identify HIV-Nef as a novel target for preventing and treating HIV- associated diseases.