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.

Keywords: hepatitis B virus; hepatocellular carcinoma; insertional mutagenesis; integration; non-homologous end joining.

Graphical abstract

Figure 1

HBV Life Cycle. The HBV life cycle, including viral entry, cccDNA formation, transcription, replication, assembly, secretion, and dslDNA integration is shown. The red arrows indicate the routes of dslDNA integration from both the de-novo-infected nucleocapsids and the cytoplasm-produced nucleocapsids. The black dotted arrow indicates the formation of cccDNA-like molecules from dslDNA. See text for detailed description. ER, endoplasmic reticulum; MVB, multivesicular body.

Figure 2

Synthesis of rcDNA and dslDNA. As the template, pgRNA is preformed for protein priming (A) mediated by the TP domain of Pol, and the (−)-DNA is subsequently synthesized (B). For the synthesis of rcDNA (C), the RNA primer is transferred to DR2 of (−)-DNA and primes the synthesis of (+)-DNA. For the synthesis of dslDNA (D), the RNA primer performs the direct (in situ) extension yielding (+)-DNA. See text for detailed description.

Figure 3

Conceptual Model for HBV DNA Integration. The dslDNA is first repaired by removing the Pol protein and the structure of the 5′ cap, after which the (+)-DNA extension is completed. Host genomic DNA double-stranded breaks can result from HBV infection or other factors. Finally, the mature dslDNA is randomly integrated into the host genome by NHEJ or MMEJ.