Dynamics of Hepatitis B Virus Covalently Closed Circular DNA: A Mini-Review

Abstract

Eradication of cccDNA is an ideal goal of chronic hepatitis B (CHB) therapy. Understanding the changes in the cccDNA pool during therapy provides a basis for developing CHB treatment strategies. On the other hand, the shift in the balance of the cccDNA pool following therapies allowed researchers to investigate the dynamics of cccDNA. Central to the description of cccDNA dynamics is a parameter called cccDNA half-life. CccDNA half-life is not an intrinsic property of cccDNA molecules, but a description of an observed phenomenon characterized by cccDNA pool decline. Since cccDNA has to be in the nuclei of host cells to function, the half-life of cccDNA is determined by the state and destiny of the host cells. The major factors that drive cccDNA decay include noncytopathic effects and hepatocyte turnover (death and division). In some cases, the determining factor is not the half-life of cccDNA itself, but rather the half-life of the hepatocyte. The main purpose of this review is to analyze the major factors affecting cccDNA half-life and determine the areas requiring further study. In addition, the discrepancy in cccDNA half-life between short-term and long-term nucleot(s)ide analog (NUC) therapy was reported. Hypotheses were proposed to explain the multi-phasic decline of cccDNA during NUC therapy, and a framework based on cccDNA dynamics was suggested for the consideration of various anti-HBV strategies.

Classifying hepatitis B therapies with insights from covalently closed circular DNA dynamics

“…The impact of these “natural forces” on the cccDNA pool in CHB patients can be unveiled by blocking cccDNA replenishment through NAs. The cccDNA pool declines with an observed half-life (as discussed in our previous study ( Hu and Huang, 2023 )). Assuming an optimistic scenario where the cccDNA pool has a half-life of 60 days, it would still require over six years to clear 10 10 cccDNA copies from the liver, even with an agent that completely halts cccDNA synthesis.…”

“…Moreover, obstructing the synthesis of more upstream rcDNA can prevent cccDNA formation, which is achievable with nucleoside analogs (NAs). As we mentioned in a previous review, there are multiple approaches for estimating the half-life of cccDNA, but the conclusions vary considerably ( Hu and Huang, 2023 ). These disparities are potentially linked to the diversity in hepatocyte lifespan.…”

“…Given that Strategy 1 does not expedite cccDNA decay, the existing cccDNA pool must decrease due to “natural forces”. In patients without an effective immune response against HBV, these “natural forces” are mainly driven by hepatocyte turnover, involving cell death and division processes ( Fourel et al., 1994 ; Zhu et al., 2001 ; Mason et al., 2009 ; Allweiss et al., 2018 ; Tu et al., 2022 ; Ding et al., 2023 ; Hu and Huang, 2023 ). The impact of these “natural forces” on the cccDNA pool in CHB patients can be unveiled by blocking cccDNA replenishment through NAs.…”

“…This biphasic decline has been observed in patients receiving various treatments, including NAs, CAMs, siRNA, and combination therapy. The first phasic decline is attributed to the decay of serum virion and the second phase is mainly driven by the turnover of infected hepatocytes or the decline of cccDNA ( Tsiang et al., 1999 ; Hu and Huang, 2023 ).…”

“…In light of this perspective, variations in cccDNA levels during treatment have paramount importance, falling under the domain of cccDNA dynamics. In a prior review, we comprehensively analyzed the factors influencing cccDNA dynamics and introduced a preliminary classification of hepatitis B treatment strategies based on these dynamics ( Hu and Huang, 2023 ).…”