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.

Towards HBV curative therapies

“…cccDNA is either originated from new incoming virions or amplified from encapsidated rcDNA from the hepatocyte cytoplasm. Because hepatocytes have a long half‐life (>6‐months or even years), the half‐life of cccDNA is also relatively long; therefore, elimination of cccDNA by hepatocyte turnover is not a major means of clearance . Reverse transcriptase nucleoside analogue (NA) inhibitors have a negligible effect on cccDNA formation, stability or amplification, and therefore HBV commonly rebounds after cessation of treatment with NA .…”

“…Because hepatocytes have a long half-life (>6-months or even years), the half-life of cccDNA is also relatively long; therefore, elimination of cccDNA by hepatocyte turnover is not a major means of clearance. 72 Reverse transcriptase nucleoside analogue (NA) inhibitors have a negligible effect on cccDNA formation, stability or amplification, and therefore HBV commonly rebounds after cessation of Several in vitro studies demonstrate that it is possible to degrade cccDNA in the nucleus of hepatocytes with minimal hepatotoxicity effect. As discussed above, programmable RNA-guided DNA endonucleases, including CRISPR/Cas9 system have shown in both cell and mouse models the potential to serve as effective tool for the depletion of the cccDNA pool in HBV-infected hepatocytes ( Table 2).…”

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

“…It is stable, and is responsible for long term viral persistence, even after years of Pol inhibitor therapy and suppression of all detectable viral DNA in the circulation (Alweiss and Dandri, 2017). Thus, targeting cccDNA is considered the most important goal in the field of anti-HBV drug design (Alter et al, 2018).…”

Modeling the dynamics of hepatitis B infection, immunity, and drug therapy

“…106 By contrast, only 1-3 copies of cccDNA were reported in human infections. [107][108][109] Mathematical models and experimental studies have investigated the role of cccDNA, in particular the contribution of recycling and loss through cell division in disease maintenance or resolution. 19,20,23,[110][111][112] Computational studies have investigated the possibility of cccDNA removal through gene therapy 113 ; while others proposed phenomena for cccDNA maintenance inside a cell, with recycling and amplification versus superinfection being proposed as explanatory mechanisms.…”