Approximately 257 million people are living with hepatitis B infection worldwide. Hepatitis B is caused by the hepatitis B virus of the hepadnaviridae family which is a DNA virus. The virus is transmitted through the parenteral route with exposure to infected bodily fluids and replicates in hepatocytes (liver cells). Hepatitis B is a disease of the liver with symptoms including jaundice, light or grey stools, hepatic tenderness and enlargement of the liver (hepatomegaly). While most adults recover, 90% of infants, 30-50% of children between the ages 1 and 5 years and 5% of adults with the disease progress to chronic HBV that causes serious diseases such as cirrhosis and hepatocellular carcinoma. The development of chronic HBV is established through persistence of the virus due to the formation of covalently closed circular DNA (cccDNA). Wei and Ploss showed in their study for the first time how cccDNA is formed from relaxed circular DNA (rcDNA).
The genome of the virion is a double-stranded relaxed circular DNA with four lesions. These lesions are the covalently linked viral polymerase and DNA flap on the 5’-end of the negative strand and the 5’-capped RNA primer and ssDNA gap on the positive strand. After entry through the bile acid transporter (NTCP), the viral rcDNA is released into the nucleus and the four lesions on the rcDNA are repaired to form a stable cccDNA. In addition to establishing chronicity, cccDNA serves as a template for the HBV viral transcripts. Both viral factors and host repair factors are involved in the repair process. Though Wei and Ploss identified the human factors involved in this process namely proliferating cell nuclear antigen (PCNA), the replication factor C (RFC) complex, DNA polymerase delta, flap endonuclease 1 (FEN-1), and DNA ligase 1 (LIG1), the exact mechanism by which these lead to the repair of the four lesions was not known. In their recently published work, they first showed that all five human factors are necessary for the repair of the lesions on the positive strand, whereas only FEN-1 and LIG1 are required to repair the lesions on the negative strand. Then they proceeded to understand the repair mechanism of each strand individually by monitoring the intermediates. The removal of the covalently attached viral polymerase was found to be required in the repair process with the product deproteinated rcDNA a critical repair intermediate. This research shows that the repair of the positive and negative strands are independent events with the positive strand repair resembling the maturation of Okazaki fragments. The negative-strand repair process involves a slow removal of 5’ protein adduct and removal of the DNA flap by FEN-1 leaving a nick that subsequently seals.
This remarkable work is going to be very essential in the development of therapeutics for chronic HBV infection.
-Bethel
https://www.nature.com/articles/s41467-021-21850-9
https://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html
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