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

• 批准号: 8577616
• 负责人: YANG-XIN FU
• 金额: $ 49.99万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577616
• 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; young adult

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治疗慢性HBV感染的新型免疫治疗方法。目前还没有治愈3.5亿已经慢性感染B型肝炎病毒（HBV）的患者的方法。抗HBV药物可有效抑制HBV复制，但HBsAg仍由HBV cccDNA或整合的基因组表达。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组的四个关键新进展：i）具有人类免疫系统的新型人源化小鼠模型&人类肝脏（AFC 8-hu HSC/Hep小鼠），其支持人源化肝脏中的HBV感染、免疫应答、肝炎和纤维化; iii）新开发的免疫活性新生小鼠和年轻成年小鼠中的AAV/HBV 1.3模型;和iv）克服肝脏中免疫耐受的基于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HB 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。通过互补的专业知识，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感染如何调节体内肝脏和脾脏/LN中的人T细胞功能？(ii)HBV持续存在和PD 1/TIM 3在肝脏免疫应答受损中的作用是什么？(iii)Ad-LIGHT-HBs疫苗接种（含HBs清除mAb和抗病毒药物）是否能够治愈正在进行的HBV感染？(iv)preS 1是一个比HBsAg更好的靶点来破坏耐受性以诱导HBV中和抗体吗？这些问题的答案将对该领域产生重大影响。关键的发现将在HBV感染患者和未来的临床试验中得到证实。