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治疗慢性乙肝病毒感染的新的免疫治疗方法。目前，已经有3.5亿慢性乙肝病毒(乙肝病毒)感染者无法治愈。抗-HBs药物能有效抑制HBVDNA复制，但HBVcccDNA或整合基因组仍能表达HBSAg。由于缺乏相关的动物模型，导致慢性感染、免疫反应、肝纤维化/肝硬变和肝癌等慢性肝病的发病机制尚不清楚。该项目将利用PI小组的四项关键新进展：i)新型人源化小鼠模型-人免疫系统-人肝脏(AFC8-Hu HSC/Hep小鼠)，支持乙肝病毒感染、免疫反应、肝炎和人源化肝脏纤维化；ii)与HBs Ag高亲和力的人源单抗(MAb)，在体内能够中和乙肝病毒并清除细胞外HBs；iii)新开发的AAV/HBV1.3模型用于具有免疫能力的新生和青年小鼠；以及iv)克服肝脏免疫耐受的光治疗性疫苗方法。我们推测，通过用抗病毒药物和高亲和力的HBs mAb降低乙肝病毒粒子/乙肝表面抗原，光基乙肝治疗性疫苗将有效地打破乙肝病毒诱导的免疫耐受，诱导抗乙肝免疫，治愈乙肝病毒感染。凭借互补的专业知识，这两个PI将解决以下与乙肝病毒诱导的免疫病理学和免疫疗法相关的具体问题：(I)在活体中，乙肝病毒感染如何调节人体肝和脾/LN中的T细胞功能？(Ii)乙肝病毒持续存在和PD1/TIM3在人体肝脏免疫反应受损中的作用是什么？(3)接种Ad-Light-HBs疫苗(带有HBs清除单抗和抗病毒药物)是否能够治愈持续的乙肝病毒感染？(Iv)在打破耐受性以诱导乙肝病毒中和抗体方面，PreS1是否是比HBSAg更好的靶点？这些问题的答案将对该领域产生重大影响。这一关键发现将在感染乙肝病毒的患者身上得到证实，并在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.