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Insights into Hepatitis B Virus DNA Integration-55 Years after Virus Discovery.

ABSTRACT: Hepatitis B virus (HBV), which was discovered in 1965, is a threat to global public health. HBV infects human hepatocytes and leads to acute and chronic liver diseases, and there is no cure. In cells infected by HBV, viral DNA can be integrated into the cellular genome. HBV DNA integration is a complicated process during the HBV life cycle. Although HBV integration normally results in replication-incompetent transcripts, it can still act as a template for viral protein expression. Of note, it is a primary driver of hepatocellular carcinoma (HCC). Recently, with the development of detection methods and research models, the molecular biology and the pathogenicity of HBV DNA integration have been better revealed. Here, we review the advances in the research of HBV DNA integration, including molecular mechanisms, detection methods, research models, the effects on host and viral gene expression, the role of HBV integrations in the pathogenesis of HCC, and potential treatment strategies. Finally, we discuss possible future research prospects of HBV DNA integration.

SUBMITTER: Zhao K

PROVIDER: S-EPMC8454683 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Insights into Hepatitis B Virus DNA Integration-55 Years after Virus Discovery.

Zhao Kaitao K Liu Andrew A Xia Yuchen Y

Innovation (Cambridge (Mass.)) 20200805 2

Hepatitis B virus (HBV), which was discovered in 1965, is a threat to global public health. HBV infects human hepatocytes and leads to acute and chronic liver diseases, and there is no cure. In cells infected by HBV, viral DNA can be integrated into the cellular genome. HBV DNA integration is a complicated process during the HBV life cycle. Although HBV integration normally results in replication-incompetent transcripts, it can still act as a template for viral protein expression. Of note, it is ...[more]

PMID: 34557710

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Project description:BackgroundHBV DNA integration into the host genome is frequently found in HBV-associated HCC tissues and is associated with hepatocarcinogenesis. Multiple detection methods, including hybrid capture-sequencing, have identified integration sites and provided clinical implications; however, each has advantages and disadvantages concerning sensitivity, cost, and throughput. Therefore, methods that can comprehensively and cost-effectively detect integration sites with high sensitivity are required. Here, we investigated the efficiency of RAISING (Rapid Amplification of Integration Site without Interference by Genomic DNA contamination) as a simple and inexpensive method to detect viral integration by amplifying HBV-integrated fragments using virus-specific primers covering the entire HBV genome.Methods and resultsIllumina sequencing of RAISING products from HCC-derived cell lines (PLC/PRF/5 and Hep3B cells) identified HBV-human junction sequences as well as their frequencies. The HBV-human junction profiles identified using RAISING were consistent with those determined using hybrid capture-sequencing, and the representative junctions could be validated by junction-specific nested PCR. The comparison of these detection methods revealed that RAISING-sequencing outperforms hybrid capture-sequencing in concentrating junction sequences. RAISING-sequencing was also demonstrated to determine the sites of de novo integration in HBV-infected HepG2-NTCP cells, primary human hepatocytes, liver-humanized mice, and clinical specimens. Furthermore, we made use of xenograft mice subcutaneously engrafted with PLC/PRF/5 or Hep3B cells, and HBV-human junctions determined by RAISING-sequencing were detectable in the plasma cell-free DNA using droplet digital PCR.ConclusionsRAISING successfully profiles HBV-human junction sequences with smaller amounts of sequencing data and at a lower cost than hybrid capture-sequencing. This method is expected to aid basic HBV integration and clinical diagnosis research.

Dataset Information

Insights into Hepatitis B Virus DNA Integration-55 Years after Virus Discovery.

Publications

Insights into Hepatitis B Virus DNA Integration-55 Years after Virus Discovery.

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