Immune Mechanisms of Elevated Liver Diseases During HIV Infection

项目总结 HIV-增强型肝病的病毒学和免疫机制(Hold) 在CART或HAART下由HIV-1感染引起的肝病，而不是乙肝病毒/丙型肝炎重叠感染 普遍研究不足，并构成严重的健康问题，因为在估计的3800万艾滋病毒中，有一半- 受感染的人目前在购物车里。艾滋病毒引起的炎症在CART期间未完全消除 并可能增加患肝病的风险。缺乏研究艾滋病毒的小动物模型-- 增强的肝病阻碍了我们剖析病毒学和免疫学机制的能力， 并有效地测试新的治疗方法。我的实验室在多次迭代中创造或改进了人性化 可以移植有功能的人类免疫系统和人类肝细胞的小鼠模型，如 HepSC。根据我们最近的发现，在持续的HIV/CART期间，HU-HSC/HEP模型发展， 这将使我们能够系统地描述Hold的机制。 该项目的长期目标是阐明艾滋病毒的病毒和免疫学机制。 加强人类肝病(HOLD)和开发新的治疗方法(IFNAR封闭抗体/Bab和 M2巨噬细胞抑制物)在新型人源化小鼠模型中的应用 星状细胞(Hu-HSC/HepSC小鼠)。具体地说，我们将实现以下与艾滋病毒有关的里程碑- 增强型肝病：(I)人类免疫缺陷病毒增强型肝病(Hold)模型的建立/优化 HSC/HepSC小鼠在HIV/CART过程中；(Ii)阐明HIV-1感染的病毒和免疫学机制 诱导M2致病巨噬细胞加重肝脏疾病；(Iii)确定HIV诱导的干扰素-I的作用 和M2巨噬细胞在艾滋病毒增强的肝纤维化中的作用；以及(Iv)IFNAR Bab和M2抑制剂的开发 治疗HIV/CART相关的肝病。该项目的发现将对 了解HIV诱导的促进肝病的机制并寻找新的靶点 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.