HBV-Integration Studies in the Clinic: Role in the Natural History of Infection

Abstract

Hepatitis B virus (HBV) infection is a major global health problem causing acute and chronic liver disease that can lead to liver cirrhosis and hepatocellular carcinoma (HCC). HBV covalently closed circular DNA (cccDNA) is essential for viral replication and the establishment of a persistent infection. Integrated HBV DNA represents another stable form of viral DNA regularly observed in the livers of infected patients. HBV DNA integration into the host genome occurs early after HBV infection. It is a common occurrence during the HBV life cycle, and it has been detected in all the phases of chronic infection. HBV DNA integration has long been considered to be the main contributor to liver tumorigenesis. The recent development of highly sensitive detection methods and research models has led to the clarification of some molecular and pathogenic aspects of HBV integration. Though HBV integration does not lead to replication-competent transcripts, it can act as a stable source of viral RNA and proteins, which may contribute in determining HBV-specific T-cell exhaustion and favoring virus persistence. The relationship between HBV DNA integration and the immune response in the liver microenvironment might be closely related to the development and progression of HBV-related diseases. While many new antiviral agents aimed at cccDNA elimination or silencing have been developed, integrated HBV DNA remains a difficult therapeutic challenge.

Keywords: HBV DNA integration; HBsAg; HBx; chronic hepatitis B; double-stranded DNA breaks; hepatitis B virus infection; oxidative stress.

Figure 1

Natural history of hepatitis B. The natural history of chronic hepatitis B has been schematically divided into five clinical or virological phases (according to European Association for the Study of the Liver 2017 guidelines); +, rarely detected; ++, occasionally detected; +++, often detected; ++++, frequently detected; +++++, almost always detected.

Figure 2

Role of HBV DNA integration in liver disease and HCC development. The HBV double-stranded linear DNA (dslDNA) obtained after the plus-strand DNA extension is completed is the main substrate for HBV DNA integration. HBV dslDNA can integrate into the host cell genome at the sites of cellular double-stranded DNA breaks by nonhomologous end joining (NHEJ) or microhomology-mediated end joining (MMEJ) repair pathways depending on the sequence characteristics at the ends of the viral DNA and the host double-stranded break DNA. Integration of HBV DNA sequences into the host genome as well as prolonged production of HBx and HBsAg and/or of modified forms of HBx and preS/S envelope proteins may contribute to viral infection persistence and to liver damage via multiple mechanisms, which ultimately lead to liver cancer development.