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.

项目摘要/摘要： 尽管有有效的疫苗可用，慢性乙肝(CHB)仍然是一个重大的公共卫生负担 以及批准的治疗方法。清除乙肝表面抗原的功能性治疗是目前乙肝治疗的终点。虽然 延长核素类似物治疗可抑制HBVdna复制，功能治愈率 仍然很低。在功能治愈的情况下，预计肝内cccdna将处于转录水平。 非活动状态，与整合的HBVDNA(IDNA)状态无关。我们和其他人提供了证据 IDNA是乙肝表面抗原的主要来源，尤其是在HBeAg阴性的慢性乙肝患者。现行的血清检测方法 不能区分肝内cccDNA和IDNA产生的乙肝表面抗原。在本提案中，我们重点关注1) 慢性乙型病毒性肝炎患者外周血中cccDNA和IDNA浓度及转录活性的研究 2)评估cccDNA和IDNA转录中的表观遗传机制在治疗反应中的作用； 3)比较肝内和血浆中的IDNA水平，并将IDNA水平与HBs Ag滴度和 治疗结果；4)评估第二代血清HBVpgRNA和新的HBVcAg 生物标志物作为cccDNA的替代标志物；5)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的cccDNA和乙肝表面抗原丢失的预测因子。这是一个独一无二的 利用特征良好的肝脏和血液样本以及高级分子进行的翻译研究 了解乙肝病毒持续、不活跃和感染的病毒学机制 通行证。我们研究的成功将对领先的新疗法的开发产生重大影响 彻底治愈乙肝病毒。