Modeling of hepatitis B virus kinetics and accumulation of cccDNA in primary human hepatocytes
Bibliographic record
Abstract
Background & Aims Knowledge about early HBV covalently closed circular DNA (cccDNA) accumulation post infection is lacking. We characterized and mathematically modeled HBV infection kinetics during early infection and treatment in primary human hepatocytes (PHHs). Methods PHHs were inoculated with HBV, and infection was monitored with and without treatment with the nucleoside analog entecavir (ETV), the HBV-entry inhibitor Myr-preS1, or both ETV + Myr-preS1. Extracellular HBV DNA (exHBV), total intracellular HBV DNA (inHBV), and cccDNA were frequently measured during the 12 days post inoculation. A multicompartmental mathematical model was developed to explain HBV infection dynamics. Results Multiphasic exHBV and inHBV kinetics were overall similar in untreated and Myr-preS1-treated PHHs. In ETV-treated PHHs (either alone or with Myr-preS1), exHBV and inHBV initially declined and did not resurge. ETV-treated cultures had significantly ( p =0.002) lower mean cccDNA levels at Day 2 post inoculation (4.3 ± 0.1 vs . 4.7 ± 0.1) and reached plateau slower (5 vs . 2 days) than untreated and Myr-preS1-treated cultures, respectively. Modeling predicts that the recycling of inHBV into cccDNA stops when cccDNA reaches a maximum and HBV secretion changes depending on the concentration of inHBV. Even when initiated at the time of inoculation, ETV did not prevent or eradicate infection but rather blocked inHBV accumulation gradually, reaching 97% efficacy by the end of the 12-day experiment and resulting in an average 44% slower cccDNA accumulation. Conclusions The study provides insight into the interrelationships and dynamics of cccDNA accumulation, inHBV accumulation, and secretion of exHBV containing particles. Although kinetics and modeling support the conclusion that the level of cccDNA in the cell is regulated, the mechanisms that determine HBV capsid secretion vs . recycling to the nucleus for cccDNA accumulation require further investigation. Impact and implications: Using primary human hepatocytes (PHHs), we characterize early HBV kinetics post infection. HBV-infected PHH were treated with an entry inhibitor to characterize the accumulation of intracellular and extracellular HBV DNA and the nuclear episomal viral genome called covalently closed circular DNA (cccDNA) in the absence of HBV spread. Kinetic and mathematical modeling in PHHs confirms that the replication inhibitor, entecavir, strongly blocks intracellular HBV DNA accumulation, which also slowed the accumulation of cccDNA. However, modeling indicates that effects on cccDNA accumulation are not directly determined by intracellular HBV DNA levels, supporting the conclusion that cccDNA levels within the cell are regulated in some yet-to-be-elucidated manner.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".