HBV cccDNA and integrated DNA in HIV coinfection and HBV monoinfection

HIV 合并感染和 HBV 单一感染中的 HBV cccDNA 和整合 DNA

• 批准号: 10882266
• 负责人: Haitao Guo
• 金额: $ 84.74万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-03 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10882266
• 关键词: Acceleration; Affect; Biological Assay; Biological Markers; Biopsy Specimen; Blood; Blood specimen; Cells; Chronic Hepatitis B; Cirrhosis; Clinical; Clinical Treatment; DNA; DNA Integration; DNA Methylation; DNA Microarray Chip; DNA biosynthesis; Data; Development; Disease Progression; Epigenetic Process; Evaluation; Extrahepatic; Generations; Genetic Transcription; Goals; HIV; HIV Infections; Hepatic; Hepatitis B; Hepatitis B Core Antigen; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B e Antigens; Histones; Immune response; Liver; Methods; Molecular; Monitor; Pathway interactions; Patients; Persons; Phosphorylation; Plasma; Prediction of Response to Therapy; Primary carcinoma of the liver cells; Production; Promoter Regions; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Sequence Analysis; Serology; Serum; Source; Statistical Methods; Surface; Surrogate Markers; Technology; Transcript; Translational Research; Treatment outcome; Vaccines; Viral; Viral Genes; Virus Diseases; Virus Replication; analog; bisulfite sequencing; co-infection; end stage liver disease; environmental change; epigenetic marker; histone methylation; improved; innovation; integration site; intrahepatic; liver biopsy; methylation biomarker; molecular diagnostics; new therapeutic target; novel; novel therapeutics; pgRNA; research study; responders and non-responders; success; tool; transcriptome sequencing; treatment responders; treatment response; viral DNA; viral RNA; virus core

Project summary/ Abstract: Chronic hepatitis B (CHB) remains a substantial public health burden despite the availability of effective vaccines and approved therapies. Functional cure with HBsAg clearance is the current HBV treatment endpoint. Although prolonged therapy with nucleos(t)ide analogs can suppress HBV DNA replication, the rate of functional cure remains low. With functional cure, it is expected that the intrahepatic cccDNA would be in a transcriptional inactive state regardless the status of the integrated HBV DNA (iDNA). We and others provided evidence that the iDNA produces a major source of HBsAg especially in HBeAg-negative CHB. The current serum assay cannot distinguish HBsAg generated from intrahepatic cccDNA versus iDNA. In this proposal, we focus to 1) evaluate both the concentrations and the transcriptional activities of cccDNA and iDNA in CHB with and without HIV; 2) assess the roles of epigenetic mechanisms in cccDNA and iDNA transcription in treatment response; 3) compare the intrahepatic and plasma iDNA levels, and to correlate iDNA levels with HBsAg titers and treatment outcomes; 4) evaluate second generation serum HBV pgRNA and novel HBV core Ag (HBcAg) biomarkers as surrogate markers for cccDNA; 5) apply the clinical, serological and virological parameters to generate predictors of treatment-induced transcriptionally inactive cccDNA and HBsAg loss. This is a unique translational research study that utilize well-characterized liver and blood samples as well as advanced molecular technologies and methods to understand the virological mechanisms of HBV persistence, inactivity, and clearance. The success of our study will have significant impacts in the development of novel therapies leading to a complete HBV cure.

项目概要/摘要： 尽管有有效的疫苗，慢性乙型肝炎（CHB）仍然是一个巨大的公共卫生负担 和批准的疗法。 HBsAg 清除的功能性治愈是当前 HBV 治疗终点。虽然 长期使用核苷（酸）类似物治疗可以抑制 HBV DNA 复制，提高功能性治愈率 仍然很低。通过功能性治愈，预计肝内 cccDNA 将处于转录状态 无论整合的 HBV DNA (iDNA) 的状态如何，都处于非活动状态。我们和其他人提供的证据表明 iDNA 是 HBsAg 的主要来源，特别是在 HBeAg 阴性 CHB 中。目前的血清检测 无法区分肝内 cccDNA 和 iDNA 生成的 HBsAg。在本提案中，我们重点关注 1) 评估 CHB 中 cccDNA 和 iDNA 的浓度和转录活性，无论是否使用 艾滋病病毒; 2）评估cccDNA和iDNA转录的表观遗传机制在治疗反应中的作用； 3) 比较肝内和血浆 iDNA 水平，并将 iDNA 水平与 HBsAg 滴度相关联 治疗结果； 4)评估第二代血清HBV pgRNA和新型HBV核心Ag(HBcAg) 生物标记物作为 cccDNA 的替代标记物； 5) 应用临床、血清学和病毒学参数 生成治疗引起的转录失活 cccDNA 和 HBsAg 丢失的预测因子。这是一个独特的 利用充分表征的肝脏和血液样本以及先进的分子技术进行转化研究 了解 HBV 持续存在、不活动和传播的病毒学机制的技术和方法 清除。我们研究的成功将对领先的新疗法的开发产生重大影响 从而彻底治愈乙肝病毒。