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The Role of HBeAg in HBV Persistence

HBeAg 在 HBV 持续存在中的作用

基本信息

批准号：
10219794
负责人：
Haitao Guo
金额：
$ 39.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219794
关键词：
Affect Anabolism Antiviral Agents Arginine Binding Binding Proteins Biochemistry Blood C-terminal Cell Culture Techniques Cell Nucleus Cell physiology China Chinese People Chronic Chronic Hepatitis B Circular DNA Cirrhosis Clinical Immunology Collaborations Core Protein DNA Binding Dendritic Cells Development Disease Excision Failure Gene Expression Genetic Transcription Genome Goals Hepatitis B Hepatitis B Virus Hepatitis B e Antigens Homologous Gene Human Herpesvirus 4 Immune Immune Tolerance Immune system Immunology Immunosuppression Immunosuppressive Agents Immunotherapy In Vitro Individual Infection Innate Immune Response Interferon Type II Interferon-alpha Interferons Lead Light Longevity Maintenance Malignant neoplasm of liver Mediating Molecular Biology Myeloid-derived suppressor cells N-terminal Natural Killer Cells Nuclear Nucleosomes Pathway interactions Patients Peptide Signal Sequences Peripheral Blood Mononuclear Cell Population Production Protein Precursors Proteins Proteomics Public Health Reporting Research Research Project Grants Resistance Response Elements Risk Factors Role Scientist Shapes Signal Transduction Structure Surface Antigens T-Cell Proliferation T-Lymphocyte Technology Tryptophan 2,3 Dioxygenase United States Up-Regulation Viral Viral Genome Virus Virus Diseases Virus Replication adaptive immune response base cell type chronic infection cytokine design effective therapy exhaustion indoleamine innovation interest liver function macrophage monocyte novel novel therapeutics restoration seroconversion success therapy development tool viral DNA viral genomics virus host interaction

项目摘要

ABSTRACT Chronic hepatitis B virus (HBV) infection remains a significant public health burden affecting approximately 240 million individuals worldwide and at least 1.2 million in the United States, and is endemic in China where 8-9% of the populations are infected. Chronic hepatitis B (CHB) is one of the leading risk factors of cirrhosis and the deadly liver cancer. Therefore it is important to elucidate the mechanism of HBV persistence and find a cure for chronic hepatitis B. The development of HBV persistence is due to the failure of host immune system to clear the virus infection, and the longevity of the persistent form of HBV DNA genome, which is the covalently closed circular (ccc) DNA in a nuclear minichromosome structure. In this research project, we will set out to elucidate the role of the understudied hepatitis B e antigen (HBeAg) in HBV persistence. HBeAg positivity and high titer reflect the high level of HBV replication and immune tolerance in CHB patients. HBeAg seroconversion is usually considered to be a beneficial milestone and evidence of reduced viral replication. Our preliminary observations revealed the followings: (1) The numbers of circulating monocytic myeloid-derived suppressor cells (mMDSCs) in immune tolerant CHB patients are higher than healthy controls and immune active patients; HBeAg induces the expansion of mMDSCs and the upregulation of immune suppressor molecules including indoleamine 2,3- dioxynase (IDO) in mMDSCs, which in turn inhibit T cell proliferation and IFN-gamma production, suggesting that the HBeAg may induce immune tolerance/suppression through activation of mMDSC; (2) The intracellular HBeAg intermediate (p22), but not the supernatant mature HBeAg, inhibits the activity of interferon-sensitive response element (ISRE) and interferon-stimulated gene (ISG) expression under interferon-alpha (IFN-α) stimulation, suggesting that p22 may blunt IFN signaling to help the virus to evade innate immune response and become resistant to IFN therapy; (3) The nuclear localization of p22 indicates that, reminiscent of the HBeAg homologue HBV core protein which has been shown to bind cccDNA, the p22 may interact with cccDNA minichromosome and regulate its stability and/or transcription. By making use of a battery of HBV-related molecular biology, immunology, biochemistry, and proteomics technologies, and several innovative cell culture tools specially designed for HBeAg and cccDNA studies, we propose to further elucidate the mechanisms of the HBeAg-mMDSC-IDO axis-induced T cell suppression and the intracellular HBeAg-mediated blockage of IFN signaling, and the potential association of nuclear HBeAg with cccDNA and its function will be determined and compared to core protein. The accomplishment of this project will shed light on the mechanism of HBV persistence, and ultimately lead to the development of novel therapeutics to break the virus-induced immune tolerance and reset/reactivate the immune system to clear HBV infection.

摘要慢性B型肝炎病毒（HBV）感染仍然是一个重大的公共卫生负担，影响约240 在世界范围内有100万人，在美国至少有120万人，在中国有8-9%的人的人口被感染。慢性B型肝炎（CH B）是肝硬化的主要危险因素之一，致命的肝癌因此，阐明HBV持续存在的机制并找到治疗HBV感染的方法是非常重要的。慢性B型肝炎。HBV持续存在的发展是由于宿主免疫系统未能清除病毒感染，和持久形式的HBV DNA基因组的寿命，这是共价封闭的，在核微型染色体结构中的环状（ccc）DNA。在这个研究项目中，我们将着手阐明未充分研究的B e抗原（HBeAg）在HBV持续存在中的作用。HBeAg阳性和高滴度反映了CHB患者体内HBV复制水平和免疫耐受水平的高水平。HBeAg血清转换通常是这被认为是一个有益的里程碑和减少病毒复制的证据。我们的初步观察结果显示：（1）外周血单核细胞髓源性抑制细胞（mMDSC）在免疫耐受的CHB患者中高于健康对照和免疫活性患者; HBeAg诱导 mMDSC的扩增和免疫抑制分子包括吲哚胺2，3- 二氧合酶（IDO），这反过来又抑制T细胞增殖和IFN-γ的产生，这表明 HBeAg可能通过激活mMDSC诱导免疫耐受/抑制;（2）细胞内 HBeAg中间体（p22），而不是上清液成熟HBeAg，抑制干扰素敏感性干扰素-α（IFN-α）作用下的反应元件（ISRE）和干扰素刺激基因（ISG）表达刺激，表明p22可以钝化IFN信号，以帮助病毒逃避先天免疫应答，（3）p22的核定位表明，与HBeAg阳性细胞相比，已显示与cccDNA结合的同源HBV核心蛋白，p22可与cccDNA相互作用微小染色体并调节其稳定性和/或转录。通过使用一组HBV相关的分子生物学、免疫学、生物化学和蛋白质组学技术，以及几种创新的细胞培养特别为HBeAg和cccDNA研究设计的工具，我们建议进一步阐明 HBeAg-mMDSC-IDO轴诱导的T细胞抑制和细胞内HBeAg介导的IFN阻断将确定细胞核HBeAg与cccDNA及其功能的潜在关联，与核心蛋白质相比。本课题的完成将为进一步研究HBV的发病机制提供理论依据持久性，并最终导致新的治疗方法的发展，以打破病毒诱导的免疫耐受性和重置/重新激活免疫系统以清除HBV感染。