Hepatitis B virus (HBV) infection poses a global health challenge, with hundreds of millions experiencing chronic infections. Unlike many other viruses, HBV establishes a persistent presence within infected liver cells, leading to long-term complications like cirrhosis and liver cancer. A central factor enabling this chronicity is covalently closed circular DNA (cccDNA). This stable viral genome resides in the nucleus of infected cells, acting as a persistent template for viral activity. Understanding cccDNA is key to comprehending the challenges in managing chronic HBV infection.
What is cccDNA?
Covalently closed circular DNA (cccDNA) is a distinct molecular form of the hepatitis B virus genome that plays a key role in establishing and maintaining chronic infection. It is a double-stranded DNA molecule that forms a closed loop, residing in the nucleus of an infected liver cell. This circular and supercoiled structure provides it with high stability, making it resistant to degradation by cellular enzymes.
The formation of cccDNA occurs early in the viral life cycle after the virus enters a liver cell. The incoming viral DNA, which is partially double-stranded and relaxed circular (rcDNA), is transported to the cell’s nucleus. Host cellular enzymes then repair the gaps and incomplete strands of the rcDNA, converting it into the stable cccDNA molecule. This process establishes a persistent viral reservoir within the infected cell.
The stability of cccDNA is a hallmark feature, allowing it to endure for the entire lifespan of the infected hepatocyte. An infected liver cell may contain between 1 to 10 copies of cccDNA molecules. This persistence is a key reason why chronic HBV infection is so difficult to clear, as cccDNA provides a continuous source for viral production, even when active viral replication is suppressed by medications.
How cccDNA Drives Viral Infection
The cccDNA molecule serves as the blueprint for ongoing production of new hepatitis B viruses within an infected cell. Residing in the nucleus, it acts as a transcriptional template, directing the host cell’s machinery to create various viral RNA molecules. These RNAs enable the virus to multiply and spread.
One type of RNA transcribed from cccDNA is pregenomic RNA (pgRNA). This RNA molecule is reverse-transcribed by the viral polymerase to produce new copies of the viral DNA genome. These newly synthesized genomes are then packaged into new viral particles, which can infect other healthy liver cells or contribute to the cccDNA pool in the already infected cell.
Beyond pgRNA, cccDNA also directs the synthesis of other subgenomic RNAs. These RNAs are translated into various viral proteins, including the core protein, surface antigens, and the viral polymerase. These proteins are necessary for assembling new viral particles. The continuous transcription from cccDNA ensures a steady supply of these components, driving sustained viral replication and maintaining the chronic infection.
Why cccDNA Challenges Treatment
The enduring nature of cccDNA presents a major barrier to achieving a complete cure for chronic hepatitis B infection. Current antiviral therapies, such as nucleos(t)ide analogs (NAs), suppress HBV replication by inhibiting the viral polymerase enzyme. These drugs reduce circulating virus and prevent disease progression, but they do not directly eliminate or significantly reduce the established cccDNA pool within infected liver cells.
Because cccDNA persists untouched by current treatments, infected cells can continue to produce viral RNAs and proteins, albeit at a reduced rate. Individuals with chronic HBV often require lifelong therapy to keep the virus under control. If antiviral treatment is discontinued, the cccDNA reservoir can reactivate, leading to a rebound in viral replication.
The inability of current drugs to eradicate cccDNA is the primary reason why a “functional cure” for HBV, defined as sustained undetectable viral load and loss of viral surface antigen after treatment cessation, remains an elusive goal. Researchers are pursuing new therapeutic strategies that target cccDNA, aiming to eliminate it from infected cells, silence its transcriptional activity, or promote its degradation. These approaches are the next frontier for a cure for chronic hepatitis B.