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

基本信息

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
项目类别：
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

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

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项目摘要

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：尽管有效疫苗，但慢性肝炎B（CHB）仍然是一个巨大的公共卫生负担并批准疗法。 HBSAG清除率的功能固化是当前的HBV处理终点。虽然用核（T）IDE类似物长时间治疗可以抑制HBV DNA复制，功能治愈的速率保持低。使用功能性治疗，可以预期肝内CCCDNA将在转录中无活性状态不管综合HBV DNA（IDNA）的状态如何。我们和其他人提供了证据表明 IDNA产生了HBSAG的主要来源，尤其是在HBEAG阴性CHB中。当前的血清测定法无法区分肝内CCCDNA与IDNA产生的HBSAG。在此提案中，我们将重点放在1）评估CCCDNA和IDNA在CHB中的浓度和转录活性，艾滋病病毒; 2）评估表观遗传机制在CCCDNA和IDNA转录中的作用； 3）比较肝内和等离子体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）生物标志物作为CCCDNA的替代标记； 5）将临床，血清学和病毒学参数应用于生成治疗诱导的转录无活性CCCDNA和HBSAG丢失的预测指标。这是一个独特的翻译研究，利用良好的肝脏和血液样本以及晚期分子了解HBV持久性，不活动性和清除。我们研究的成功将对领先的新疗法的发展产生重大影响完整的HBV治疗。