The Role of HBeAg in HBV Persistence

HBeAg 在 HBV 持续存在中的作用

• 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
• 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

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.

抽象的 慢性乙型肝炎病毒 (HBV) 感染仍然是一个重大的公共卫生负担，影响约 240 人 全球有 100 万人，美国至少有 120 万人，在中国流行，其中 8-9% 的人群受到感染，慢性乙型肝炎（CHB）是肝硬化和肝硬化的主要危险因素之一。 因此，阐明乙型肝炎病毒持续存在的机制并找到治疗方法非常重要。 慢性乙型肝炎。乙型肝炎病毒持续存在是由于宿主免疫系统未能清除 病毒感染以及 HBV DNA 基因组持久形式的寿命（共价闭合） 在这个研究项目中，我们将着手阐明核微型染色体结构中的环状（ccc）DNA。 正在研究的乙型肝炎 e 抗原 (HBeAg) 在 HBV 持续性和高滴度中的作用。 反映慢性乙型肝炎患者中乙型肝炎病毒复制水平较高且免疫耐受性通常较高。 我们的初步观察被认为是一个有益的里程碑和减少病毒复制的证据。 揭示了以下内容：（1）循环单核骨髓源性抑制细胞（mMDSC）的数量 免疫耐受的慢性乙型肝炎患者的感染率高于健康对照者和免疫活跃的 HBeAg 患者； mMDSC 的扩增和免疫抑制分子（包括吲哚胺 2,3-）的上调 mMDSC 中的双加氧酶 (IDO)，进而抑制 T 细胞增殖和 IFN-γ 产生，表明 (2)细胞内 HBeAg 中间体 (p22)，但不是上清液成熟的 HBeAg，抑制干扰素敏感的活性 干扰素-α (IFN-α) 下的反应元件 (ISRE) 和干扰素刺激基因 (ISG) 表达 刺激，表明 p22 可能会减弱 IFN 信号传导，帮助病毒逃避先天免疫反应， (3) p22 的核定位表明，让人想起 HBeAg 同源 HBV 核心蛋白已被证明可结合 cccDNA，p22 可能与 cccDNA 相互作用 微小染色体并通过使用 HBV 相关的电池来调节其稳定性和/或转录。 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 专门为 HBeAg 和 cccDNA 研究设计的工具，我们建议进一步阐明其机制 HBeAg-mMDSC-IDO 轴诱导的 T 细胞抑制和细胞内 HBeAg 介导的 IFN 阻断 信号传导，核 HBeAg 与 cccDNA 的潜在关联及其功能将被确定并 与核心蛋白相比，该项目的完成将揭示乙肝病毒的机制。 持久性，并最终导致治疗小说的发展，以打破病毒诱导的免疫系统 耐受性并重置/重新激活免疫系统以清除 HBV 感染。

项目成果

Intrahepatic transcriptomics reveals gene signatures in chronic hepatitis B patients responded to interferon therapy.

肝内转录组学揭示了慢性乙型肝炎患者对干扰素治疗有反应的基因特征。

• 发表时间: 2022-12
• 影响因子: 13.2
• 作者: Li, Ning;Yu, Kangkang;Dong, Minhui;Wang, Jinyu;Yang, Feifei;Zhu, Haoxiang;Yu, Jie;Yang, Jingshu;Xie, Wentao;Mitra, Bidisha;Mao, Richeng;Wu, Feizhen;Guo, Haitao;Zhang, Jiming
• 通讯作者: Zhang, Jiming

Effect of nucleos(t)ide analogues on blood lipid profiles in patients with chronic hepatitis B: A cross-sectional survey.

核苷（酸）类似物对慢性乙型肝炎患者血脂谱的影响：横断面调查。

• 发表时间: 2022-12-16
• 影响因子: 1.6
• 作者: Chen, Jing Wen;Cao, Xiong Yue;Qi, Xun;Zhang, Ji Ming
• 通讯作者: Zhang, Ji Ming