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

基本信息

批准号：
10252170
负责人：
Zandrea Ambrose
金额：
$ 19.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10252170
关键词：
Acquired Immunodeficiency Syndrome Address Adenovirus Vector Animal Model Anti-Retroviral Agents Antiviral 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 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 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 virology

项目摘要

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 2.6 亿人患有慢性乙型肝炎病毒 (HBV) 感染，这会导致一系列疾病肝脏病理，包括慢性肝炎、肝硬化和肝细胞癌 (HCC)。乙型肝炎病毒感染继续传播，并导致全球 40% 的 HCC 死亡。近3800万人全球范围内都感染了人类免疫缺陷病毒 (HIV)，其中约 10% 长期感染感染了乙型肝炎病毒。 HIV/HBV 合并感染的发病率和死亡率高于单一感染和合并感染感染会加速 HBV 相关肝病，更频繁地发展为 HCC，尤其是当 CD4 计数很低。随着时间的推移，病毒学受到抑制的共感染个体的肝纤维化程度仍会加剧可能是由于即使在艾滋病毒感染受到抑制期间也会发生持续的慢性炎症。没有可以治愈 HBV 或 HIV。关于 HIV/HBV 合并感染，包括自然 HBV 疾病，仍有多个悬而未决的问题肝病的病程和评估、隐匿性感染后 HBV 再激活（在没有 HBV DNA 的情况下）主动复制），以及两种病毒的抗病毒治疗的改进。阻止 HIV/HBV 双重感染发病机制和治疗研究目前缺乏可靠的动物模型来研究合并感染。临床前模型对于评估感染机制以及新的预防方法、改进的方法至关重要疗法和治疗策略。我们建议对植入人源化肝脏和免疫系统的新型嵌合小鼠进行表征非胎儿人类细胞和组织。此外，我们将评估 HBV 复制和肝病进展在单一感染期间以及 CD4 细胞耗竭或抗病毒治疗期间。此外，我们还将评估 HIV/HBV 合并感染，无论是否接受抑制性抗病毒治疗。目标是改进人性化鼠标模型可重现人类 HBV 单一感染和 HIV/HBV 混合感染，以更好地开发疗法和治疗策略。