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.
Highlights
In contrast to acute hepatitis (AH), characterized by robust and multispecific antiviral immune responses, which contribute to viral clearance, chronic Hepatitis B virus (HBV) infection is characterized by an adaptive immune response that rarely results in virus elimination [8]
Once chronic infection is established, the inflammatory response sustained by antiviral T lymphocytes and non-antigen specific inflammatory cells can significantly increase the risk of developing liver disease including chronic hepatitis, cirrhosis, and hepatocellular carcinoma
During the last few years, knowledge in the HBV DNA integration field has greatly improved owing to the development of new detection methods and research models
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. In contrast to AH, characterized by robust and multispecific antiviral immune responses, which contribute to viral clearance, chronic HBV infection is characterized by an adaptive immune response that rarely results in virus elimination [8] This failure may be due, in part, to the tolerogenic properties of the liver microenvironment that are able to suppress the antiviral immune responses [9,10], and to an impaired and dysfunctional HBV-specific T-cell response due to virus production of extremely high levels of HBsAg and hepatitis B e antigen (HBeAg), in the early phase of the infection [8,11,12,13,14].
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