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: 10240509
• 负责人: Lishan Su
• 金额: $ 38.63万
• 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/10240509
• 关键词: Address; Affect; Animal Model; Blocking Antibodies; Cells; Chronic; Development; Disease; Disease Progression; Disease model; Exhibits; Goals; HIV; HIV Infections; HIV-1; Health; Hepatic Stellate Cell; Hepatitis B Virus; Hepatitis C co-infection; Hepatocyte; Highly Active Antiretroviral Therapy; Human; Human immunodeficiency virus test; IFNAR1 gene; Immune; Immune system; Immunologics; Impairment; Infection; Inflammation; Interferons; Kinetics; Liver; Liver Fibrosis; Liver diseases; Modeling; Mus; Myelogenous; Pathogenicity; Pathology; Patients; Risk; Role; Severities; Signal Transduction; Testing; Viral; Work; antiretroviral therapy; base; humanized mouse; improved; in vivo; inhibitor/antagonist; macrophage; mouse model; novel; novel therapeutics; prevent; receptor; single-cell RNA sequencing; stellate cell; virology

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.

项目概要 HIV 增强性肝病的病毒学和免疫机制 (HELD) cART 或 HAART 治疗下 HIV-1 感染引起的肝脏疾病，且没有 HBV/HCV 合并感染， 普遍没有得到充分研究，并造成严重的健康问题，因为估计 3800 万艾滋病毒感染者中有一半 感染者目前正在接受 cART，HIV 引起的炎症在 cART 期间尚未完全解决。 并可能导致肝脏疾病风险增加。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， 并有效地测试新的疗法，经过多次迭代，人性化。 可以植入功能性人类免疫系统和人类肝细胞的小鼠模型，例如 HepSC。根据我们最近的发现，Hu-HSC/Hep 模型在持续的 HIV/cART 期间发展为 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）并开发新疗法（IFNAR 阻断抗体/bAb 和 M2巨噬细胞抑制剂）在具有人类免疫和人类肝脏的新型人源化小鼠模型中 具体来说，我们将实现与 HIV 相关的以下里程碑： 增强型肝病：（i）在Hu-中建立/优化HIV增强型肝病（HELD）模型 HIV/cART 期间的 HSC/HepSC 小鼠；(ii) 阐明 HIV-1 的病毒和免疫机制 诱导 M2 致病性巨噬细胞加剧肝脏疾病；(iii) 确定 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；以及 (iv) IFNAR bAb 和 M2 抑制剂的开发 治疗 HIV/cART 相关的肝脏疾病 该项目的研究结果将对治疗产生重大影响。 了解艾滋病毒诱导的促进肝病的机制并发现新的靶点 开发新疗法。