Novel Concepts in Mechanisms Modulating HBV Persistence, Pathogenesis and Oncogenetic Properties

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Background

So far, it has been estimated that 2 billion individuals have been infected by hepatitis B virus (HBV). Among them, 250 million have developed a chronic infection and are at risk to develop cirrhosis and hepatocellular carcinoma. Every year, 1 million individuals die for these end-stage liver diseases. After the entry into the hepatocytes, viral genome migrates to the nucleus where it is converted into the so called circular covalently closed DNA (cccDNA). cccDNA acts as a mini-chromosome, allowing HBV to establish persistent infection in the form of chronic and occult infection. Chronic HBV infection is a dynamic process deriving from the delicate balance between the extent of HBV intrahepatic reservoir and the strength of the immune system. Furthermore, despite the availability of an effective vaccine, chronic HBV infection still remains an important driver of hepatocarcinogenesis.

In endemic areas for HBV, 70-80% cases of liver cancer are caused by this virus. So far, the currently available anti-HBV drugs (mainly represented by inhibitors of the Reverse Transcriptase enzyme) can only suppress viral replication but cannot eradicate the infection. Furthermore, these drugs can reduce but cannot abrogate the risk to develop HBV-induced hepatocellular carcinoma. Beyond chronic infection, HBV can establish occult infection. In the setting of occult infection, immune responses suppress the transcriptional activity of cccDNA thus favouring the entry into a latent or minimally-replicating status. Occult HBV infection is intensively investigated since it can give origin to HBV reactivation during conditions of immunesuppression and can act as an important cofactor in the onset of hepatocellular carcinoma. Indeed, occult HBV infection maintains the same pro-oncogenic properties of over infection, including the capability to integrate into host genome, to produce pro-oncogenic proteins and to contribute to a mild but persistent inflammation.

Despite the availability of effective vaccine and potent antiviral drugs, so far there are still unsolved issues related to HBV infection. Firstly, mechanisms underlying the persistence of cccDNA have not been fully elucidated. Understanding this issue is critical also in the light of developing innovative therapeutic approaches aimed at achieving HBV cure. Intriguingly, unlike other aetiologies, HBV-induced hepatocellular carcinoma can occur also in the absence of cirrhosis and in young adults, highlighting the existence of direct HBV prooncogenetic properties. HBV-DNA integration in cell genome is considered a key event in hepatocarcinogenesis. Nevertheless, the downstream effects, triggered by HBV-DNA integration, on cell proliferation have not been clarified yet. Viral genetic variability can also modulate HBV oncogenic potential. In particular, the accumulation of stop-codons or deletions in the gene encoding surface glycoproteins can determine the production of structurally aberrant forms that are retained inside the cells leading to oxidative stress and increased cell proliferation. Nevertheless, despite several efforts, a fine mapping of viral genetic markers capable to modulate HBV oncogenetic potential is lacking. Defining these aspects is crucial in order to decipher the fine mechanisms underlying HBV oncogenetic potential and to identify novel biomarkers to identify patients at higher risk to develop liver cancer who need more intensive liver monitoring. Finally, the role of hepatitis delta virus (HDV) superinfection in promoting HBV-driven hepatocarcinogenesis has not been fully clarified.

This article collection is aimed at providing new insights on:

• Mechanisms underlying HBV persistence, cccDNA production and homeostasis as well as its control by the immune system.
• Mechanisms modulating the establishment of the occult HBV infection
• Mechanisms unravelling the oncogenetic properties of occult HBV infection
• Mechanisms underlying HBV-DNA integration and its impact on human gene expression and intracellular pathways
• Factors promoting HBV-DNA integration
• Pro-oncogenetic properties of HBV proteins
• Unravelling the impact of occult HBV infection in promoting hepatocytes neoplastic transformation
• The impact of viral genetic variability in modulating HBV oncogenetic potential
• The role of classical and innovative serum biomarkers in predicting the risk of HBV driven hepatocellular carcinoma
• The role of HDV in favoring the progression of chronic HBV infection towards hepatocellular carcinoma

Keywords: HBV, hepatocellular carcinoma, integration, mutations, serum biomarkers

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