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： 慢性B型肝炎（CH B）仍然是一个巨大的公共卫生负担，尽管有效的疫苗的可用性 和批准的疗法HBsAg清除的功能性治愈是目前的HBV治疗终点。虽然 核苷（酸）类似物长期治疗可抑制HBV DNA复制，功能性治愈率 仍然很低。在功能性治愈的情况下，预期肝内cccDNA将处于转录水平。 无论整合的HBV DNA（iDNA）的状态如何，都处于非活性状态。我们和其他人提供了证据， iDNA产生HBsAg的主要来源，特别是在HBeAg阴性的CHB中。目前的血清检测 不能区分肝内cccDNA与iDNA产生的HBsAg。在本提案中，我们重点关注1） 评估在CHB中cccDNA和iDNA的浓度和转录活性， 2）评估治疗反应中cccDNA和iDNA转录中表观遗传机制的作用; 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核心抗原（HBcAg） 生物标志物作为cccDNA的替代标志物; 5）将临床、血清学和病毒学参数应用于 产生治疗诱导的转录失活cccDNA和HBsAg丢失的预测因子。这是一个独特 转化研究，利用良好表征的肝脏和血液样本以及先进的分子生物学技术， 技术和方法，以了解HBV持续存在，不活动， 间隙我们研究的成功将对开发新疗法产生重大影响， 完全治愈乙肝病毒