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

摘要 大约2.6亿人患有慢性乙肝病毒(乙肝病毒)，这导致了一系列 肝脏病理，包括慢性肝炎、肝硬变和肝细胞癌。乙肝病毒感染 继续传播，占全球所有肝细胞癌死亡病例的40%。近3800万人 全球都感染了人类免疫缺陷病毒(HIV)，其中约10%的人慢性共患病 感染了乙肝病毒。艾滋病毒/乙肝病毒混合感染的发病率和死亡率高于单一感染和联合感染。 感染加速了与乙肝病毒相关的肝病，肝细胞癌的发生频率更高，尤其是当 数量很少。随着时间的推移，病毒学抑制的联合感染者仍然会经历肝纤维化的增加 可能是由于持续的慢性炎症，即使在被抑制的艾滋病毒感染期间也会发生。没有 治愈乙肝病毒或艾滋病病毒。 关于艾滋病毒/乙肝病毒混合感染，包括自然的乙肝病毒病，仍有许多悬而未决的问题 肝病的病程和评估，隐匿性感染后乙肝病毒的重新激活(在没有HBVDNA的情况下 主动复制)，以及针对这两种病毒的抗病毒治疗的改进。阻碍艾滋病毒/乙肝病毒混合感染 发病机制和治疗研究缺乏可靠的动物模型来研究合并感染。临床前 模型是评估感染机制以及改进的新预防方法的关键 治疗方法和治疗策略。 我们建议对植入人源化肝脏和来自 非胎儿人体细胞和组织。此外，我们还将评估乙肝病毒复制和肝病进展。 在单一感染期间，使用CD4细胞耗尽或抗病毒治疗。此外，我们还将评估 使用抑制性抗病毒治疗或不使用抑制性抗病毒治疗的艾滋病毒/乙肝病毒混合感染。我们的目标是改进人性化鼠标 为更好地发展人类乙肝病毒单一感染和HIV/乙肝病毒混合感染的模型 治疗方法和治疗策略。

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.