Immune Mechanisms of Elevated Liver Diseases During HIV Infection

项目摘要 HIV增强性肝病（HELD）的病毒学和免疫机制 在cART或HAART下由HIV-1感染引起的肝脏疾病，无HBV/HCV合并感染， 艾滋病的研究普遍不足，并构成严重的健康问题，因为估计的3800万艾滋病毒中有一半- 感染者目前正在接受cART治疗。HIV诱导的炎症在cART期间未完全消退 并可能导致肝病风险增加。缺乏研究艾滋病毒的小动物模型- 增强型肝病（HELD）阻碍了我们剖析病毒学和免疫学机制的能力， 并有效地测试新疗法。经过多次迭代，我的实验室创造或改进了人性化的 可以移植功能性人免疫系统和人肝细胞的小鼠模型， HepSC。基于我们最近的发现，Hu-HSC/Hep模型在持续的HIV/cART期间发展出HELD， 这将使我们能够系统地描述HELD的机制。 该项目的长期目标是阐明艾滋病毒的病毒和免疫机制， 增强人类肝脏疾病（HELD）和开发新的治疗剂（IFNAR阻断抗体/bAb和 M2巨噬细胞抑制剂）在具有人免疫和人肝细胞的新型人源化小鼠模型中的作用 星状细胞（Hu-HSC/HepSC小鼠）。具体而言，我们将实现以下与艾滋病毒有关的里程碑： 增强型肝病：（i）在Hu中建立/优化HIV增强型肝病（HELD）模型， 在HIV/cART期间HSC/HepSC小鼠;（ii）阐明HIV-1通过其 诱导M2致病性巨噬细胞加重肝脏疾病;（iii）定义HIV诱导的IFN-I的作用 和M2巨噬细胞在HIV增强的肝纤维化中的作用;和（iv）IFNAR bAb和M2抑制剂的开发 治疗HIV/cART相关肝病。该项目的结果将对以下方面产生重大影响： 了解艾滋病毒诱导的机制，促进肝脏疾病和发现新的目标， 开发新的治疗方法

PROJECT SUMMARY Virological and Immune mechanisms of HIV-enhanced liver diseases (HELD) Liver diseases caused by HIV-1 infection under cART or HAART without HBV/HCV co-infection are generally understudied and pose a serious health problem because half of the estimated 38 million HIV- infected people are currently under cART. HIV-induced inflammation is not completely resolved during cART and may contribute to the increased risk of liver diseases. The lack of small animal models to investigate HIV- enhanced liver diseases (HELD) impedes our ability to dissect the virological and immunological mechanisms, and to efficiently test new therapeutics. My lab has created or improved, over many iterations, humanized mouse models that can be engrafted with a functional human immune system and human liver cells such as HepSC. Based on our recent findings, the Hu-HSC/Hep model develops HELD during persistent HIV/cART, which will allow us to systematically characterize the mechanisms of HELD. The long-term goals of the project are to elucidate the viral and immunologic mechanisms of HIV– enhanced human liver diseases (HELD) and to develop novel therapeutics (IFNAR blocking antibody/bAb and M2 macrophage inhibitors) in the novel humanized mouse model with human immune and human hepatic stellate cells (Hu-HSC/HepSC mice). Specifically, we will achieve the following milestones related to HIV- enhanced liver diseases: (i) establishment/optimization of HIV-enhanced liver disease (HELD) models in Hu- HSC/HepSC mice during HIV/cART; (ii) elucidation of viral and immunological mechanisms by which HIV-1 induces M2 pathogenic macrophages to exacerbate liver diseases; (iii) defining the role of HIV-induced IFN-I and M2 macrophages in HIV-enhanced liver fibrosis; and (iv) development of the IFNAR bAb and M2 inhibitors to treat HIV/cART associated liver diseases. Findings from the project will have a significant impact on understanding HIV-induced mechanisms in promoting liver diseases and on discovering novel targets for developing novel therapeutics.