Pathogenesis of HIV and HBV Co-Infection in a Humanized Mouse Model

人源化小鼠模型中 HIV 和 HBV 共感染的发病机制

• 批准号: 10349595
• 负责人: Zandrea Ambrose
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10349595
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adenovirus Vector; Animal Model; Anti-Retroviral Agents; Antiviral Therapy; Area; Biocompatible Materials; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Count; Cells; Cessation of life; Chronic; Chronic Hepatitis; Chronic Hepatitis B; Cirrhosis; Clinical; Development; Disease Progression; Engraftment; Ethics; Evaluation; Genes; Goals; HIV; HIV Infections; Hematopoiesis; Hepatitis; Hepatitis B Infection; Hepatitis B Therapy; Hepatitis B Virus; Hepatocyte; Human; Immune; Immune system; Immunocompromised Host; Individual; Infection; Inflammation; Interferon-alpha; Life; Liver; Liver Fibrosis; Liver diseases; Longevity; Macaca; Methods; Modeling; Morbidity - disease rate; Mus; Na(+)-taurocholate-cotransporting peptide; Outcome; Pan Genus; Pathogenesis; Pathology; Persons; Pharmaceutical Preparations; Pre-Clinical Model; Prevention; Primary carcinoma of the liver cells; Research; Risk; Role; Time; Tissues; Vaccines; Variant; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; adaptive immunity; adeno-associated viral vector; analog; animal model development; cancer therapy; chronic infection; chronic liver disease; co-infection; experience; high risk; human disease; human fetus tissue; humanized mouse; immune function; immune reconstitution; immunodeficient mouse model; improved; liver function; mortality; mouse model; novel; novel strategies; prevent; receptor; reconstitution; response; transmission process; treatment research; vaccine access; viral DNA

Abstract Approximately 260 million people have chronic hepatitis B virus (HBV) infection, which leads to a spectrum of liver pathologies, including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). HBV infection continues to be transmitted and is responsible for 40% of all HCC deaths worldwide. Almost 38 million people are infected with human immunodeficiency virus (HIV) globally, with approximately 10% of them chronically co- infected with HBV. Morbidity and mortality in HIV/HBV co-infection is higher than mono-infections and co- infection accelerates HBV-related liver disease with more frequent development of HCC, particularly when CD4 counts are low. Virologically suppressed co-infected individuals still experience increased liver fibrosis over time possibly due to ongoing chronic inflammation that occurs even during suppressed HIV infection. There are no cures for either HBV or HIV. Multiple unanswered questions remain regarding HIV/HBV co-infections, including the natural HBV disease course and assessment of liver disease, HBV reactivation after occult infection (HBV DNA in the absence of active replication), and improvements in antiviral treatments for both viruses. Hindering HIV/HBV co-infection pathogenesis and treatment research is the lack of a reliable animal model to study co-infection. Pre-clinical models are essential to evaluate mechanisms of infection as well as novel prevention methods, improved therapies, and curative strategies. We propose to characterize novel chimeric mice engrafted with a humanized liver and immune system from nonfetal human cells and tissues. In addition, we will evaluate HBV replication and liver disease progression during mono-infection and with either CD4 cell depletion or antiviral therapy. In addition, we will evaluate HIV/HBV co-infection with or without suppressive antiviral therapy. The goal is to improve the humanize mouse model to recapitulate human HBV mono-infection and HIV/HBV co-infection for the development of better therapies and curative strategies.

抽象的 大约有2.6亿人患有慢性乙型肝病毒（HBV）感染，导致一系列 肝脏病理，包括慢性肝炎，肝硬化和肝细胞癌（HCC）。 HBV感染 继续传输，并造成全球所有HCC死亡的40％。近3800万人 全球感染了人类免疫缺陷病毒（HIV），其中约有10％的慢性共同 感染HBV。 HIV/HBV共感染中的发病率和死亡率高于单一感染和共同感染 感染加速与HBV相关的肝病，HCC的发育频繁，尤其是当CD4时 计数很低。病毒学抑制的共感染者仍然经历了随着时间的推移增加肝纤维化的增加 可能是由于持续的慢性炎症，即使在抑制HIV感染期间也会发生。没有 治愈HBV或HIV。 关于HIV/HBV共同感染的多个未解决的问题，包括天然HBV疾病 肝病的病程和评估，神秘感染后的HBV重新激活（在没有的情况下HBV DNA 主动复制），以及两种病毒的抗病毒治疗的改善。阻碍HIV/HBV共同感染 发病机理和治疗研究缺乏可靠的动物模型来研究共感染。临床前 模型对于评估感染机制以及新型预防方法至关重要，改进了 疗法和治疗策略。 我们建议表征新型的嵌合小鼠，这些小鼠植入了人源化的肝脏和免疫系统 非fet人类细胞和组织。此外，我们将评估HBV复制和肝病进展 在单感染期间以及CD4细胞耗竭或抗病毒疗法。此外，我们将评估 艾滋病毒/HBV共同感染，有或没有抑制性抗病毒疗法。目标是改善人性化鼠标 概括人类HBV单感染和HIV/HBV共同感染的模型以发展更好 疗法和治疗策略。