HIV, HCV, Hippo, and Liver Disease Progression

大约30%的艾滋病毒阳性者会同时感染丙型肝炎病毒。人们已经很好地认识到艾滋病毒感染 在丙型肝炎病毒合并感染的情况下加速肝纤维化的进展，尽管其背后的确切机制 还没有完全阐明。虽然在丙型肝炎病毒的直接作用抗病毒(DAA)疗法方面取得了很大进展， 单是艾滋病毒感染就越来越被认为是导致肝纤维化的原因之一。肝病仍排在第二位 在活跃的抗逆转录病毒治疗时代，艾滋病毒阳性患者的常见死因。此外，进行性肝纤维化通常是 直到肝硬变和/或其并发症的后遗症叠加，才能认识到，在DAA可以逆转 调查结果。缺乏阻止纤维化进展的治疗方法进一步加剧了这一现实。揭开 因此，HIV感染者纤维化进展的潜在机制和确定新的靶点是很高的 优先考虑。YAP/TAZ是调节细胞增殖的河马信号通路中的关键中间体。在河马 在“ON”状态下，YAP/TAZ在细胞质中被磷酸化，导致YAP/TAZ失活，细胞衰老或 细胞凋亡。在河马“关闭”状态下，YAP/TAZ转位到细胞核，调节细胞增殖和纤维化形成。 此外，YAP/TAZ还通过感知细胞外基质(ECM)的密度来响应ECM信号，从而进一步 增强纤维化形成。因此，较硬的ECM诱导了YAP/TAZ核定位，导致肝星状。 细胞(HSC)活化和纤维化形成，进一步加重纤维化。 在早期的工作中，我们证明了艾滋病毒通过反应性调节加强了丙型肝炎病毒驱动的促纤维化程序。 肝细胞和肝干细胞中的氧物种，核因子-κB和转化生长因子β-1。YAP/TAZ途径也与 转化生长因子β1途径，AS YAP/TAZ也可以作为机械感受器，通过直接结合来调节转化生长因子β1信号传导 YAP/TAZ到SMAD蛋白，作为人类胚胎干细胞中ECM僵硬的函数。重要的是 转化生长因子β-1通路在艾滋病毒/丙型肝炎合并感染中的纤维化进展提示YAP/TAZ在 在HIV中调节肝病的进展。为此，我们已经证明了HIV可以诱导YAP/TAZ调节 促纤维化基因在肝干细胞中的表达，而丙型肝炎病毒可以在肝细胞中做同样的事情。此外，上游的几个目标 已知YAP/TAZ与HIV及其蛋白结合，进一步提示YAP/TAZ与HIV的肝病发病机制有关。 然而，缺乏关于这些关联的详细研究。鉴于YAP/TAZ与转化生长因子β1的重叠， YAP/TAZ的机械调节功能，转化生长因子β-1在艾滋病毒相关性肝纤维化中的重要性，以及已知的上游 YAP/TAZ与HIV相互作用的靶点，我们假设YAP/TAZ在HIV相关肝脏的发病机制中起关键作用 纤维化症。我们将通过以下具体目标处理这些关系：(1)确定YAP/TAZ的贡献 丙型肝炎病毒和其他肝病背景下肝纤维化的通路激活；(2)确定其机制(S) HIV在有/没有丙型肝炎病毒的情况下诱导YAP/TAZ激活的机制；以及(3)确定细胞外基质对 HIV介导的YAP/TAZ激活。通过阐明艾滋病毒、丙型肝炎病毒、YAP/TAZ和转化生长因子β之间的关系， 这项提议可能会发现抗纤维化药物的新靶点。

Coinfection with HCV occurs in approximately 30% of HIV-positive persons. It has been well recognized that HIV infection accelerates liver fibrosis progression in the setting of HCV coinfection, although the precise mechanisms underlying this have not been fully elucidated. While great advances have been made in direct acting antiviral (DAA) therapy for HCV, HIV infection alone has increasingly been recognized as a cause of liver fibrosis. Liver disease remains the second most common cause of death in HIV-positive individuals in the active ART era. In addition, progressive hepatic fibrosis is often not recognized until cirrhosis and/or sequelae from its complications have supervened, long after DAAs can reverse the findings. This reality is further compounded by the lack of therapies that halt fibrosis progression. Uncovering the mechanisms underlying fibrosis progression and identifying new targets in HIV infected persons are therefore a high priority. YAP/TAZ are critical intermediates in the Hippo signaling pathway that regulate cell proliferation. In the Hippo “on” state, YAP/TAZ are phosphorylated in the cytoplasm, leading to inactivation of YAP/TAZ and cell senescence or apoptosis. In the Hippo “off” state, YAP/TAZ translocates to the nucleus and regulates cell proliferation and fibrogenesis. In addition, YAP/TAZ also respond to extracellular matrix (ECM) cues by sensing the density of the ECM to further augment fibrogenesis. Thus, YAP/TAZ nuclear localization has been induced by stiffer ECM, leading to hepatic stellate cell (HSC) activation and fibrogenesis, further aggravating fibrosis. In earlier work, we demonstrated that HIV accentuates an HCV-driven profibrogenic program, mediated through reactive oxygen species, NF-κB and TGFβ1, in both hepatocytes and HSCs. The YAP/TAZ pathway also converges with the TGFβ1 pathway, as YAP/TAZ can also act as mechanoreceptors that regulate TGFβ1 signaling via direct binding of YAP/TAZ to SMAD proteins, as a function of the stiffness of the ECM in human embryonic stem cells. The importance of the TGFβ1 pathway in fibrosis progression in HIV/HCV coinfection suggests that YAP/TAZ plays a critical role in mediating liver disease progression in HIV. To this end, we have demonstrated that HIV can induce YAP/TAZ-regulated profibrogenic gene expression in HSCs, and HCV can do the same in hepatocytes. In addition, several targets upstream of YAP/TAZ are known to bind to HIV and its proteins, further implicating YAP/TAZ in liver disease pathogenesis in HIV. However, detailed studies regarding these associations are lacking. Given the overlap of YAP/TAZ with TGFβ1, the mechanoregulatory function of YAP/TAZ, the importance of TGFβ1 in HIV-related liver fibrosis, and the known upstream targets of YAP/TAZ that interact with HIV, we hypothesize that YAP/TAZ is pivotal to the pathogenesis of HIV-related liver fibrosis. We will address these relationships through the following Specific Aims: (1) define the contribution of YAP/TAZ pathway activation to hepatic fibrogenesis in the context of HCV and other liver diseases; (2) determine the mechanism(s) by which HIV induces YAP/TAZ activation with/without HCV; and (3) define the contribution of the extracellular matrix to HIV-mediated YAP/TAZ activation. By clarifying the relationship between HIV, HCV, YAP/TAZ, and TGFβ, the studies in this proposal are likely to uncover new targets for antifibrotic agents.