Immune Mechanisms of Elevated Liver Diseases During HIV Infection

HIV 感染期间肝病升高的免疫机制

• 批准号: 10359221
• 负责人: Lishan Su
• 金额: $ 27.92万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359221
• 关键词: Immune; Mechanisms; Elevated; Liver; Diseases

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.

项目摘要 HIV增强肝病的病毒学和免疫机制（HEN） 没有HBV/HCV共同感染的CART或HAART引起的HIV-1感染引起的肝病是 通常理解并构成严重的健康问题，因为估计3800万HIV中的一半 被感染的人目前处于手推车之下。艾滋病毒诱导的感染未完全解决。 并可能导致肝病的风险增加。缺乏研究HIV的小动物模型 增强的肝脏疾病（持有）阻碍了我们剖析病毒学和免疫学机制的能力， 并有效测试新疗法。我的实验室已经创建或改进了许多迭代，人性化 可以用功能性人体免疫系统和人肝细胞（例如）植入的小鼠模型 hepsc。根据我们最近的发现，HU-HSC/HEP模型在持续的艾滋病毒/购物车期间开发 这将使我们能够系统地表征持有的机制。 该项目的长期目标是阐明艾滋病毒的病毒和免疫机制 增强的人肝病（HOND）并开发新的疗法（IFNAR阻断抗体/BAB和 M2巨噬细胞抑制剂）在具有人类免疫和人肝的新型人性化小鼠模型中 星状细胞（HU-HSC/HEPC小鼠）。具体而言，我们将达到与HIV相关的以下里程碑 增强的肝脏疾病：（i）HU- 艾滋病毒/购物车期间的HSC/HEPC小鼠； （ii）阐明HIV-1的病毒和免疫学机制 诱导M2致病性巨噬细胞加剧肝病； （iii）定义HIV诱导的IFN-I的作用 和HIV增强肝纤维化中的M2巨噬细胞； （iv）开发IFNAR BAB和M2抑制剂 治疗HIV/CART相关的肝病。该项目的发现将对 了解艾滋病毒引起的促进肝病的机制以及发现新的目标 发展新型疗法。