{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:03:36Z","timestamp":1782281016564,"version":"3.54.5"},"posted":{"date-parts":[[2025,2,7]]},"group-title":"Systems Biology","reference-count":24,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:00:00Z","timestamp":1738886400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Chronic hepatitis B virus (HBV) infection poses a significant global health threat, causing severe liver diseases including cirrhosis and hepatocellular carcinoma. We characterized HBV DNA kinetics in primary human hepatocytes (PHH) over 32 days post-inoculation (pi) and used agent-based modeling (ABM) to gain insights into HBV lifecycle and spread. Parallel PHH cultures were mock-treated or HBV entry inhibitor Myr-preS1 (6.25 \u03bcg\/mL) was initiated 24h pi. In untreated PHH, 3 viral DNA kinetic patterns were identified: (1) an initial decline, followed by (2) rapid amplification, and (3) slower amplification\/accumulation. In the presence of Myr-preS1, viral DNA and infected cell numbers in phase 3 were effectively blocked, with minimal to no increase. This suggests that phase 2 represents viral amplification in initially infected cells, while phase 3 corresponds to viral spread to na\u00efve cells. The ABM reproduced well the HBV kinetic patterns observed and predicted that the viral eclipse phase lasts between 18 and 38 hours. After the eclipse phase, the viral production rate increases over time, starting with a slow production cycle of 1 virion per day, which gradually accelerates to 1 virion per hour after 3 days. Approximately 4 days later, virion production reaches a steady state production rate of 4 virions\/hour. The estimated median efficacy of Myr-preS1 in blocking HBV spread was 91% (range: 90-92%). The HBV kinetics and the predicted estimates of the HBV eclipse phase duration and HBV production cycles in PHH are similar of those predicted in uPA\/SCID mice with human livers.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>\n                    While primary human hepatocytes (PHH) are the most physiologically relevant culture system for studying HBV infection\n                    <jats:italic>in vitro<\/jats:italic>\n                    , comprehensive understanding of HBV infection kinetics and spread in PHH is lacking. In this study, we characterize HBV viral kinetics and employ agent-based modeling (ABM) to provide quantitative insights into the HBV production cycle and viral spread in PHH. The ABM provides an estimate of HBV eclipse phase duration, HBV production cycles and Myr-preS1 efficacy in blocking HBV spread in PHH. The results resemble those predicted in uPA\/SCID mice with human livers, demonstrating that estimated HBV infection kinetic parameters in PHH\n                    <jats:italic>in vitro<\/jats:italic>\n                    mirrors that observed in\n                    <jats:italic>in vivo<\/jats:italic>\n                    HBV infection chimeric mouse model.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.05.636596","type":"posted-content","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T20:20:23Z","timestamp":1738959623000},"source":"Crossref","is-referenced-by-count":0,"title":["Modeling of hepatitis B virus infection spread in primary human hepatocytes"],"prefix":"10.64898","author":[{"given":"Zhenzhen","family":"Shi","sequence":"first","affiliation":[{"name":"The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Tsuge","sequence":"additional","affiliation":[{"name":"The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA"},{"name":"Liver Center, Hiroshima University Hospital, Hiroshima, Japan"},{"name":"Department of Gastroenterology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholson","family":"Collier","sequence":"additional","affiliation":[{"name":"Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA"},{"name":"Decision and Infrastructure Sciences, Argonne National Laboratory, Argonne, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasue","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Hepatitis Information Center, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuro","family":"Uchida","sequence":"additional","affiliation":[{"name":"Division of Travel Medicine and Health, Research Center for GLOBAL and LOCAL Infectious Diseases, Oita University, Yufu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn M.","family":"Rutter","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Research Center, Hutchinson Institute for Cancer Outcomes Research, Biostatistics Program, Public Health Sciences Division, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Teraoka","sequence":"additional","affiliation":[{"name":"Gastroenterology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5691-1557","authenticated-orcid":false,"given":"Susan","family":"Uprichard","sequence":"additional","affiliation":[{"name":"The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Ishida","sequence":"additional","affiliation":[{"name":"PhoenixBio Co., Ltd., Higashi-Hiroshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chise","family":"Tateno","sequence":"additional","affiliation":[{"name":"PhoenixBio Co., Ltd., Higashi-Hiroshima, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Ozik","sequence":"additional","affiliation":[{"name":"Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA"},{"name":"Decision and Infrastructure Sciences, Argonne National Laboratory, Argonne, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3357-1817","authenticated-orcid":false,"given":"Harel","family":"Dahari","sequence":"additional","affiliation":[{"name":"The Program for Experimental & Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Chayama","sequence":"additional","affiliation":[{"name":"Hiroshima Institute of Life Sciences, Hiroshima, Japan"},{"name":"RIKEN Center for Integrative Medical Sciences, Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041100011572000_2025.02.05.636596v1.1","unstructured":"Organization WH. 9 April 2024. 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