HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site

Abstract

Hepatitis B virus (HBV), one of the well-known DNA oncogenic viruses, is the leading cause of hepatocellular carcinoma (HCC). In infected hepatocytes, HBV DNA can be integrated into the host genome through an insertional mutagenesis process inducing tumorigenesis. Dissection of the genomic features surrounding integration sites will deepen our understanding of mechanisms underlying integration. Moreover, the quantity and biological activity of integration sites may reflect the DNA damage within affected cells or the potential survival benefits they may confer. The well-known human genomic features include repeat elements, particular regions (such as telomeres), and frequently interrupted genes (e.g., telomerase reverse transcriptase [i.e. TERT], lysine methyltransferase 2B [i.e. KMT2B], cyclin E1 [CCNE1], and cyclin A2 [CCNA2]). Consequently, distinct genomic features within diverse integrations differentiate their biological functions. Meanwhile, accumulating evidence has shown that viral proteins produced by integrants may cause cell damage even after the suppression of HBV replication. The integration-derived gene products can also serve as tumor markers, promoting the development of novel therapeutic strategies for HCC. Viral integrants can be single copy or multiple copies of different fragments with complicated rearrangement, which warrants elucidation of the whole viral integrant arrangement in future studies. All of these considerations underlie an urgent need to develop novel methodology and technology for sequence characterization and function evaluation of integration events in chronic hepatitis B-associated disease progression by monitoring both host genomic features and viral integrants. This endeavor may also serve as a promising solution for evaluating the risk of tumorigenesis and as a companion diagnostic for designing therapeutic strategies targeting integration-related disease complications.