Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation to analyze extracellular viral markers

Journal Article · Mon Mar 11 00:00:00 EDT 2024 · PLoS Computational Biology (Online)

DOI:https://doi.org/10.1371/journal.pcbi.1011238· OSTI ID:2433945

Kitagawa, Kosaku ^[1]; Kim, Kwang Su ^[2]; Iwamoto, Masashi ^[3]; Hayashi, Sanae ^[4]; Park, Hyeongki ^[1]; Nishiyama, Takara ^[1]; Nakamura, Naotoshi ^[1]; Fujita, Yasuhisa ^[1]; Nakaoka, Shinji ^[5]; Aihara, Kazuyuki ^[6]; Perelson, Alan S. ^[7]; Allweiss, Lena ^[8]; Dandri, Maura ^[8]; Watashi, Koichi ^[9]; Tanaka, Yasuhito ^[4]; Iwami, Shingo ^[10]

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1. Nagoya Univ. (Japan)
2. Nagoya Univ. (Japan); Pukyong National University, Busan (Korea, Republic of)
3. Nagoya Univ. (Japan); National Institute of Infectious Diseases, Tokyo (Japan)
4. Kumamoto University (Japan)
5. Hokkaido Univ., Sapporo (Japan)
6. Univ. of Tokyo (Japan)
7. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
8. University Medical Center Hamburg-Eppendorf (Germany); German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems (Germany)
9. National Institute of Infectious Diseases, Tokyo (Japan); Tokyo Univ. of Science, Chiba (Japan)
10. Nagoya Univ. (Japan); Tokyo Univ. of Science, Chiba (Japan); Kyushu Univ., Fukuoka (Japan); Kyoto Univ. (Japan); Japanese Foundation for Cancer Research (JFCR), Tokyo (Japan); Institute of Physical and Chemical Research (RIKEN), Tokyo (Japan); Science Groove Inc., Fukuoka (Japan)

Chronic infection with hepatitis B virus (HBV) is caused by the persistence of closed circular DNA (cccDNA) in the nucleus of infected hepatocytes. Despite available therapeutic anti-HBV agents, eliminating the cccDNA remains challenging. Thus, quantifying and understanding the dynamics of cccDNA are essential for developing effective treatment strategies and new drugs. However, such study requires repeated liver biopsy to measure the intrahepatic cccDNA, which is basically not accepted because liver biopsy is potentially morbid and not common during hepatitis B treatment. We here aimed to develop a noninvasive method for quantifying cccDNA in the liver using surrogate markers in peripheral blood. We constructed a multiscale mathematical model that explicitly incorporates both intracellular and intercellular HBV infection processes. The model, based on age-structured partial differential equations, integrates experimental data from in vitro and in vivo investigations. By applying this model, we roughly predicted the amount and dynamics of intrahepatic cccDNA within a certain range using specific viral markers in serum samples, including HBV DNA, HBsAg, HBeAg, and HBcrAg. Our study represents a significant step towards advancing the understanding of chronic HBV infection. The noninvasive quantification of cccDNA using our proposed method holds promise for improving clinical analyses and treatment strategies. By comprehensively describing the interactions of all components involved in HBV infection, our multiscale mathematical model provides a valuable framework for further research and the development of targeted interventions.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)
• Grant/Contract Number: 89233218CNA000001
• OSTI ID: 2433945
• Report Number(s): LA-UR--23-28773
• Journal Information: PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 3 Vol. 20; ISSN 1553-7358
• Publisher: Public Library of Science
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Biological Science
hepatitis B virus