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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.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011238","type":"journal-article","created":{"date-parts":[[2024,3,11]],"date-time":"2024-03-11T17:42:31Z","timestamp":1710178951000},"page":"e1011238","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":21,"title":["Multiscale modeling of HBV infection integrating intra- and intercellular viral propagation to analyze extracellular viral markers"],"prefix":"10.1371","volume":"20","author":[{"given":"Kosaku","family":"Kitagawa","sequence":"first","affiliation":[]},{"given":"Kwang 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Tsuge","year":"2017","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"pcbi.1011238.ref040","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1002\/hep.29891","article-title":"Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics","volume":"68","author":"Y Ishida","year":"2018","journal-title":"Hepatology"},{"issue":"6","key":"pcbi.1011238.ref041","doi-asserted-by":"crossref","first-page":"1902","DOI":"10.1002\/hep.27357","article-title":"Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling","volume":"60","author":"J Guedj","year":"2014","journal-title":"Hepatology"},{"issue":"5","key":"pcbi.1011238.ref042","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/mt.2013.31","article-title":"Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection","volume":"21","author":"CI Wooddell","year":"2013","journal-title":"Mol Ther"},{"issue":"1","key":"pcbi.1011238.ref043","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s12876-017-0726-2","article-title":"Upcoming pharmacological developments in chronic hepatitis B: can we glimpse a cure on the horizon?","volume":"17","author":"S Alonso","year":"2017","journal-title":"BMC Gastroenterol.PubMed Central PMCID"},{"issue":"1","key":"pcbi.1011238.ref044","first-page":"1252","article-title":"An age-structured model of hepatitis B viral infection highlights the potential of different therapeutic strategies.","volume":"12","author":"F Fatehi","year":"2022","journal-title":"Sci Rep.PubMed Central PMCID"},{"issue":"1","key":"pcbi.1011238.ref045","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/S0168-8278(02)00115-0","article-title":"Viral dynamics during and after entecavir therapy in patients with chronic hepatitis B","volume":"37","author":"LM Wolters","year":"2002","journal-title":"J Hepatol"},{"issue":"2","key":"pcbi.1011238.ref046","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1172\/JCI58847","article-title":"IFN-alpha inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome","volume":"122","author":"L Belloni","year":"2012","journal-title":"J Clin Invest"},{"key":"pcbi.1011238.ref047","article-title":"Therapeutic shutdown of HBV transcripts promotes reappearance of the SMC5\/6 complex and silencing of the viral genome in vivo","author":"L Allweiss","year":"2021","journal-title":"Gut"},{"issue":"1","key":"pcbi.1011238.ref048","doi-asserted-by":"crossref","first-page":"21097","DOI":"10.1038\/s41598-020-78001-1","article-title":"Quantification and epigenetic evaluation of the residual pool of hepatitis B covalently closed circular DNA in long-term nucleoside analogue-treated patients","volume":"10","author":"F Lebosse","year":"2020","journal-title":"Sci Rep"},{"issue":"1","key":"pcbi.1011238.ref049","doi-asserted-by":"crossref","first-page":"3626","DOI":"10.1038\/s41598-018-21882-0","article-title":"Normalization of cell associated antiretroviral drug concentrations with a novel RPP30 droplet digital PCR assay.","volume":"8","author":"SR Dyavar","year":"2018","journal-title":"Sci Rep."},{"key":"pcbi.1011238.ref050","first-page":"9","article-title":"RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg","author":"CI Wooddell","year":"2017","journal-title":"Sci Transl Med"},{"issue":"9","key":"pcbi.1011238.ref051","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.15252\/emmm.201506172","article-title":"Blocking sense-strand activity improves potency, safety and specificity of anti-hepatitis B virus short hairpin RNA","volume":"8","author":"T Michler","year":"2016","journal-title":"EMBO Mol Med"},{"key":"pcbi.1011238.ref052","first-page":"49","article-title":"Benefits and risks of interferon therapy for hepatitis B","author":"R. Perrillo","year":"2009","journal-title":"Hepatology"},{"key":"pcbi.1011238.ref053","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/1479-5876-12-183","article-title":"HBsAg as an important predictor of HBeAg seroconversion following antiviral treatment for HBeAg-positive chronic hepatitis B patients.","volume":"12","author":"J Yang","year":"2014","journal-title":"J Transl Med."},{"issue":"12","key":"pcbi.1011238.ref054","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/jvh.12261","article-title":"Decline in intrahepatic cccDNA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBeAg loss","volume":"21","author":"Q Zheng","year":"2014","journal-title":"J Viral Hepat"},{"key":"pcbi.1011238.ref055","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.coviro.2018.04.004","article-title":"Virus entry and its inhibition to prevent and treat hepatitis B and hepatitis D virus infections.","volume":"30","author":"T Tu","year":"2018","journal-title":"Curr Opin Virol"},{"issue":"3","key":"pcbi.1011238.ref056","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1002\/hep.21299","article-title":"Intrahepatic levels and replicative activity of covalently closed circular hepatitis B virus DNA in chronically infected patients","volume":"44","author":"A Laras","year":"2006","journal-title":"Hepatology"},{"issue":"7","key":"pcbi.1011238.ref057","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1053\/j.gastro.2004.03.018","article-title":"Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy","volume":"126","author":"B Werle-Lapostolle","year":"2004","journal-title":"Gastroenterology"},{"issue":"44","key":"pcbi.1011238.ref058","doi-asserted-by":"crossref","first-page":"31715","DOI":"10.1074\/jbc.M113.501122","article-title":"Interleukin-1 and tumor necrosis factor-\u03b1 trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID).","volume":"288","author":"K Watashi","year":"2013","journal-title":"J Biol Chem"},{"issue":"10","key":"pcbi.1011238.ref059","doi-asserted-by":"crossref","first-page":"e1005893","DOI":"10.1371\/journal.ppat.1005893","article-title":"DNA Polymerase \u03ba Is a Key Cellular Factor for the Formation of Covalently Closed Circular DNA of Hepatitis B Virus.","volume":"12","author":"Y Qi","year":"2016","journal-title":"PLoS Pathog"},{"issue":"4","key":"pcbi.1011238.ref060","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/hep.21345","article-title":"Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens","volume":"44","author":"M Sugiyama","year":"2006","journal-title":"Hepatology"},{"issue":"9","key":"pcbi.1011238.ref061","doi-asserted-by":"crossref","first-page":"2899","DOI":"10.1128\/JCM.37.9.2899-2903.1999","article-title":"Quantitation of hepatitis B virus genomic DNA by real-time detection PCR","volume":"37","author":"A Abe","year":"1999","journal-title":"J Clin Microbiol"},{"key":"pcbi.1011238.ref062","article-title":"Droplet digital PCR improved quantification over qPCR reveals the stability of intrahepatic hepatitis B virus cccDNA.","author":"MI Sanae Hayashi","year":"2021","journal-title":"Scientific reports"},{"issue":"1","key":"pcbi.1011238.ref063","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/0378-1119(95)00389-N","article-title":"A new set of useful cloning and expression vectors derived from pBlueScript","volume":"163","author":"MP Mayer","year":"1995","journal-title":"Gene"},{"issue":"3","key":"pcbi.1011238.ref064","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i03","article-title":"Inverse Modelling, Sensitivity and Monte Carlo Analysis in R Using Package FME","volume":"33","author":"K Soetaert","year":"2010","journal-title":"Journal of Statistical Software"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011238","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T00:00:00Z","timestamp":1710979200000}}],"container-title":["PLOS Computational 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