The Role of cccDNA in HBV Maintenance

Abstract

Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide; it can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. The molecular mechanisms determining HBV persistence are not fully understood, but these appear to be multifactorial and the unique replication strategy employed by HBV enables its maintenance in infected hepatocytes. Both the stability of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the hepatocyte nucleus, and the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. Since a true cure of HBV requires clearance of intranuclear cccDNA from infected hepatocytes, understanding the mechanisms involved in cccDNA biogenesis, regulation and stability is mandatory to achieve HBV eradication. This review will summarize the state of knowledge on these mechanisms including the impact of current treatments on the cccDNA stability and activity. We will focus on events challenging cccDNA persistence in dividing hepatocytes.

Keywords: animal models; cccDNA; cell proliferation; hepatitis B virus; human liver chimeric mice.

Figure 1

Proliferation of hepatitis B virus (HBV)-infected hepatocytes leads to covalently closed circular DNA (cccDNA) loss; however, HBV-infected cells display reduced proliferation capacities. Schematic illustration of the fate of individual cccDNA molecules during cell division. Shaded cells depict infected cells with active HBV replication. The infinity symbol depicts cccDNA. While proliferating hepatocytes (on the left-hand side) clear the infection through cccDNA dilution and eventually exclusion of cccDNA from the re-forming nucleus, some infected cells seem to be refractory to cell division (right-hand side). PHH: primary human hepatocyte.