Novel therapeutic approaches to treating chronic hepatitis B virus infection

治疗慢性乙型肝炎病毒感染的新治疗方法

基本信息

批准号：
8840940
负责人：
YANG-XIN FU
金额：
$ 55.2万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840940
关键词：
Address Adenovirus Vector Adenoviruses Adult Affinity Animal Model Antibodies Antibody Affinity Antiviral Agents Biological Assay Cell physiology Chronic Chronic Disease Chronic Hepatitis B Cirrhosis Clinical Trials Fibrosis Foundations Future Genome Genomics Goals HIV Hepatitis Hepatitis B Hepatitis B Surface Antigens Hepatitis B Virus Hepatocyte Human Immune Immune Tolerance Immune response Immune system Immunity Immunization Infection Infectious hepatitides Kinetics Light Liver Liver diseases Lymphoid Malignant neoplasm of liver Mediating Modeling Monoclonal Antibodies Mus Neonatal Patients Pharmaceutical Preparations Role Signal Transduction Spleen Staging T-Lymphocyte Testing Therapeutic Tissues Vaccination Vaccines Virion Virus Diseases Virus Replication anti-hepatitis B base exhaust extracellular human monoclonal antibodies immunopathology in vivo mouse model neonate neutralizing antibody novel novel therapeutic intervention novel therapeutics prevent public health relevance response therapeutic vaccine transcriptome sequencing young adult

项目摘要

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.

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乙型肝炎病毒感染。目前，3.5 亿慢性乙型肝炎病毒 (HBV) 感染患者尚无治愈方法。抗HBV药物可以有效抑制HBV复制，但HBsAg仍然由HBV cccDNA或整合基因组表达。由于缺乏相关的动物模型，乙型肝炎引起的肝病（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 小组的四项关键新进展：i) 一种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、肝炎和纤维化在人源化肝脏中； ii) 与 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 HBs； iii) 新开发的 AAV/HBV1.3 免疫能力新生和年轻成年小鼠模型； iv) 基于 LIGHT 的治疗性疫苗方法克服了肝脏的免疫耐受。我们假设，通过使用抗病毒药物和高亲和力 HBs mAb 减少 HBV 病毒粒子/HBsAg，基于 LIGHT 的 HBV 治疗性疫苗将有效打破 HBV 诱导的免疫耐受，诱导抗 HBV 免疫并治愈 HBV 感染。凭借互补的专业知识，两位 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肝脏和脾脏/LN 中的人类 T 细胞功能？ (ii) HBV 持续存在和 PD1/TIM3 在人类肝脏免疫反应受损中发挥什么作用？ (iii) Ad-LIGHT-HBs 疫苗接种（使用 HBs 清除单克隆抗体和抗病毒药物）能否治愈持续的 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。主要发现将在乙型肝炎病毒感染患者和未来的临床试验中得到证实。