Transcriptomic Quantitation of Hepatitis B Virus Surface Antigen from Integration
通过整合对乙型肝炎病毒表面抗原进行转录组定量
基本信息
- 批准号:10724716
- 负责人:
- 金额:$ 7.58万
- 依托单位:
- 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:2023-05-11 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAntigensBiologicalBlood specimenCharacteristicsChronic Hepatitis BCircular DNACirculationClinicalClinical TrialsCohort StudiesConfidence IntervalsDNADataData AnalysesDigestionExclusionFamilyGenetic TranscriptionHepatitis BHepatitis B InfectionHepatitis B VirusHepatitis B e AntigensHepatocarcinogenesisHepatologyHumanHuman GenomeImmuneImmunosuppressionIncidenceInterruptionKnowledgeLegal patentLiverMeasurementMeasuresMethodsNorth AmericaNuclearOutcomePathogenesisPatientsPersonsPhenotypePreparationPrimary carcinoma of the liver cellsProceduresProteinsQuantitative Reverse Transcriptase PCRResearchResistanceSamplingSerumSourceSpecimenStudy of serumSurface AntigensTissue SampleTissuesTranscriptTransgenic ModelTranslational ResearchUnited States National Institutes of HealthValidationViralViral GenomeVirus Integrationcohortdeoxyguanosine triphosphatedigitalexperimental studyinsightmembernext generation sequencingnovelpromoterreference genomesimulationtranscriptomicsvalidation studiesviral DNAviral RNA
项目摘要
Project Summary
Hepatitis B virus (HBV) surface antigen (HBsAg) is a hallmark in patients with chronic HBV infection (CHB).
Given its close association with clinical outcomes in CHB patients, HBsAg seroclearance is required in
achieving an HBV functional or complete cure. Toward this direction, a major barrier is relevant to its biological
sources. Besides a nuclear reservoir of covalently closed circular DNA (cccDNA), HBsAg could also be
produced from cellular integration. Currently, the contribution of HBV integration to HBsAg remains elusive
due to the lack of a method for quantitative measurement. Transcription from integrated HBV DNA has several
characteristics, such as the retention of human sequences, an early termination, and the interruption of HBV
Core antigen. These features have been used to infer the relative abundance of integration-derived HBsAg
transcripts by qRT-PCR, digital droplet PCR (ddPCR), and next-generation sequencing (NGS). However,
these approaches require liver tissue and have limited use with blood samples from which ~50% of HBeAg-
negative patients have total HBV RNA below the lower limit of quantification of qRT-PCR. Bait-based target
enrichment in NGS could enhance the sensitivity but extensive microhomology between HBV and human
genomes lowers the efficiency. To address these issues, we have developed a novel method through multiple
technical advances from our lab, including template-dependent multiple displacement amplification (tdMDA)
(BioTechniques 2017), a novel target enrichment strategy via 7‑deaza‑dGTP‑resistant enzymatic digestion
(TEED) (BMC Res Notes 2020, patented), and a read simulation to evaluate relative abundance among
reference genomes (J Virol Methods 2022). The combination of tdMDA, TEED, and the read simulation,
termed MATESim, was applied to five CHB patient serum samples. Integration-derived transcripts accounted
for variable portions of total HBsAg transcripts, ranging from 1.8% to 94.3%. These results support the
hypothesis that MATESim would be a noninvasive method to quantitate HBsAg from integration at the level of
transcription. This hypothesis will be evaluated using patient specimens from the Hepatitis B Research
Network (HBRN). First, we will validate MATESim by studying paired serum/liver samples. HBsAg transcripts
from cccDNA and integrated HBV DNA may have different mechanisms for release to circulation. It is
unknown whether their relative abundance determined by MATESim in circulation is a recapitulation, an
underestimation, or an overestimation of liver data. This knowledge will help to interpret data from circulation
by MATESim. Second, we will study serum samples from 59 patients with defined HBV phenotypes in the
HBRN cohort. The experiment will allow us to gain insights into the magnitude and between-patient variance
of integration-derived HBsAg in this patient cohort at a 95% confidence interval. Taken together, as a non-
invasive method to quantitate integration-derived HBsAg, MATESim would be a turning point in translational
research, clinical trials, and patient management for the globally 257 million people infected with HBV.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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