HBV DNA Integration: Molecular Mechanisms and Clinical Implications

Abstract

Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies.

Comparison of overall survival between antiviral‐induced viral suppression and inactive phase chronic hepatitis B patients

“…Third, the NA group has a longer period of viral replication which eventually makes higher chance of HBV DNA integration into host genome. The higher chance of HBV DNA integration could make more genomic alterations in the NA group, which would result in the higher incidence of HCC …”

Viruses as key modulators of the TGF‐β pathway; a double‐edged sword involved in cancer

“…39,40 HBV chronic infection is currently estimated to influence almost 240 million people, globally, of which approximately 10% have an increased risk of developing cirrhosis and HCC. 4,41 Similar to HCV, HBV also interacts with the TGF-β pathway, a phenomenon mainly mediated by HBV X protein (HBx), which may exert diverse effects on the pathogenesis of the HBV-mediated liver pathologies 7,21,42,43 (Figure 3). Evidence by Murata further supported the hypothesis that the TGF-β pathway is directly involved in liver tumorigenesis, where HBx was shown to switch the target of hepatocytic TGF-β signaling from the TGFbRI/ pSmad3C/p21 anti-tumor pathway to the JNK/pSmad3L/c-Myc tumor supportive pathway in the early stages of liver carcinogenesis.…”

Extracellular HBV RNAs are heterogeneous in length and circulate as virions and capsid-antibody-complexes in chronic hepatitis B patients

“…More importantly, the association of circulating HBV RNAs with CACs or virions in hepatitis B patients suggests their pgRNA origin. As pgRNA could only be transcribed from nuclear cccDNA (covalent closed circular DNA) instead of integrated HBV DNA fragments (67–69), its levels truly reflect the number or transcription status of cccDNA, especially for patients with lower serum HBV DNA titers when receiving NAs treatment. Hence, our results here strongly suggest the circulating HBV RNAs within CACs or virions in hepatitis B patients could serve as novel biomarkers to assess efficacy of treatment.…”