Novel therapeutic approaches to treating chronic hepatitis B virus infection

描述（由申请人提供）：长期目标是开发一种新的免疫治疗方法来治疗慢性HBV感染。目前，3.5亿已感染慢性乙型肝炎病毒（HBV）的患者无法治愈。抗HBV药物可有效抑制HBV复制，但HBsAg仍通过HBV cccDNA或整合基因组表达。由于缺乏相关的动物模型，hbv诱导的肝脏疾病（包括慢性感染、免疫反应、纤维化/肝硬化和肝癌）的机制尚不清楚。该项目将利用pi小组的四个关键新进展：i)具有人类免疫系统和人类肝脏的新型人源化小鼠模型（AFC8-hu HSC/Hep小鼠），支持HBV感染，免疫反应，人源化肝脏中的肝炎和纤维化；ii)对HBsAg具有高亲和力的人单克隆抗体（mAb），可在体内中和HBV并清除细胞外HBV；iii)新建立的AAV/HBV1.3免疫功能小鼠模型；iv)克服肝脏免疫耐受的基于light的治疗性疫苗方法。我们假设，通过使用抗病毒药物和高亲和力的HBs单抗降低HBV病毒粒子/HBsAg， LIGHT-based HBV治疗性疫苗将有效打破HBV诱导的免疫耐受，诱导抗HBV免疫，治愈HBV感染。通过互补的专业知识，两个pi将解决以下与HBV诱导的免疫病理学和免疫治疗相关的具体问题：(i) HBV感染如何在体内调节人类肝脏和脾脏/LN中的T细胞功能？（ii） HBV持久性和PD1/TIM3在人类肝脏免疫反应受损中的作用是什么？（iii） Ad-LIGHT-HBs疫苗（含HBs清除单抗和抗病毒药物）是否能够治愈持续的HBV感染？（iv） preS1是否比HBsAg更能打破耐受性诱导HBV中和抗体？这些问题的答案将对该领域产生重大影响。这些关键发现将在hbv感染患者和未来的临床试验中得到证实。

DESCRIPTION (provided by applicant): The long-term goal is to develop a novel immune therapeutic approach to treating chronic HBV infection. There is currently no cure for the 350 million patients who are already chronically infected with hepatitis B virus (HBV). HBV replication can be effectively inhibited by anti-HBV drugs, but HBsAg is still expressed from HBV cccDNA or integrated genomes. The mechanisms of HBV-induced liver diseases, including chronic infection, immune responses, fibrosis/cirrhosis and liver cancer, are unclear due to a lack of relevant animal models. This project will take advantage of four key novel advancements in the PIs' groups: i) a novel humanized mouse model with human immune system & human liver (AFC8-hu HSC/Hep mice) that supports HBV infection, immune responses, hepatitis and fibrosis in the humanized liver; ii) human monoclonal antibodies (mAb) with high affinity to HBsAg that can neutralize HBV and clear extracellular HBs in vivo; iii) the newly developed AAV/HBV1.3 model in immune competent neonate and young adult mice; and iv) the LIGHT-based therapeutic vaccine approach that overcomes immune tolerance in the liver. We hypothesize that, by reducing HBV virions/HBsAg with antivirals and high affinity HBs mAb, the LIGHT-based HBV therapeutic vaccine will be effective to break HBV-induced immune tolerance, induce anti-HBV immunity and cure HBV infection. With complementary expertise, the two PIs will thus address the following specific questions related to HBV- induced immunopathology and immune therapeutics: (i) How does HBV infection modulate human T cell function in the liver and spleen/LN in vivo? (ii) What is the role of HBV persistence and PD1/TIM3 in impaired human immune responses in the liver? (iii) Will Ad-LIGHT-HBs vaccination (with HBs clearance mAb and antiviral) be able to cure an ongoing HBV infection? (iv) Is preS1 a better target than HBsAg to break tolerance to induce HBV neutralizing antibodies? Answers to these questions will have a significant impact on the field. The key findings will be confirmed in HBV-infected patients, and in future clinical trials.