cccDNA can form a dynamic pool within the nuclei, where it supports its persistence and encodes its structural proteins (including surface proteins, core proteins), polymerases and the X protein. Once formed in the cell nucleus, cccDNA is very difficult to get eliminated from infected cells and can persist continuously until the death of the host cell.
Importantly, this cccDNA is responsible for difficulty in curing the HBV infections, which can lead to chronic liver inflammation, cirrhosis, and even hepatocellular carcinoma. Once inside the nucleus, the gap in the rcDNA is repaired by the DNA repair machinery of the host cell to generate the covalently closed circular DNA (cccDNA). The genomic rcDNA of HBV is released from the nucleocapsid and, through the nuclear pore complex, enters into the nucleus of the hepatocyte. Next, the core particle (nucleocapsid) of HBV is released into the cytoplasm. During its natural life cycle, HBV enters hepatocytes by attaching to surface proteins, such as hepatocyte-associated heparan sulfate proteoglycans (HSPG) and sodium taurocholate cotransporting polypeptide (NTCP). More specifically, HBV is a hepatotropic DNA virus approximately 42 nm in diameter with particles consisting of surface proteins and core proteins surrounding a partially double-stranded, relaxed, and circular 3.2 kb genomic DNA component (called rcDNA) (additional details can be found in other reviews ). Over time, an increasing details have been discovered in regards to hepatitis B, and is now well known that HBV is a hepadnavirus. We expect to find indications of promising areas of research that require further study to eliminate cccDNA of HBV in patients.įor approximately 60 years, it has been known that hepatitis B is caused by a viral infection, and the hepatitis B virus (HBV) has been definitively identified as the causative factor. Herein, we review the anti-HBV mechanisms of IFN-α involving cccDNA modification as the most promising approaches to cure HBV infection. However, the clinical effects of eradicating cccDNA using IFN-α in the hepatocytes of patients with HBV are not proficient as well as expected and are not well understood. Of the medications currently available, only IFN-α can potentially target cccDNA.
Although effective treatment with NAs can dramatically decrease HBV proteins and DNA loads, and even promote serological conversion, cccDNA persists in the nucleus of hepatocytes due to the lack of effective anti-cccDNA drugs. Generally, NAs target the reverse transcription of HBV pregenomic RNA, but they cannot eliminate covalently-closed-circular DNA (cccDNA). Interferon-alpha (IFN-α) and nucleot(s)ide analogs (NAs) are first-line drugs for the treatment of chronic hepatitis B virus (HBV) infections.
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