{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T17:22:29Z","timestamp":1777915349567,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008421","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T00:00:00Z","timestamp":1605571200000}}],"reference-count":80,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T00:00:00Z","timestamp":1604534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Hepatitis C virus (HCV) causes acute hepatitis C and can lead to life-threatening complications if it becomes chronic. The HCV genome is a single plus strand of RNA. Its intracellular replication is a spatiotemporally coordinated process of RNA translation upon cell infection, RNA synthesis within a replication compartment, and virus particle production. While HCV is mainly transmitted via mature infectious virus particles, it has also been suggested that HCV-infected cells can secrete HCV RNA carrying exosomes that can infect cells in a receptor independent manner. In order to gain insight into these two routes of transmission, we developed a series of intracellular HCV replication models that include HCV RNA secretion and\/or virus assembly and release. Fitting our models to <jats:italic>in vitro<\/jats:italic> data, in which cells were infected with HCV, suggests that initially most secreted HCV RNA derives from intracellular cytosolic plus-strand RNA, but subsequently secreted HCV RNA derives equally from the cytoplasm and the replication compartments. Furthermore, our model fits to the data suggest that the rate of virus assembly and release is limited by host cell resources. Including the effects of direct acting antivirals in our models, we found that in spite of decreasing intracellular HCV RNA and extracellular virus concentration, low level HCV RNA secretion may continue as long as intracellular RNA is available. This may possibly explain the presence of detectable levels of plasma HCV RNA at the end of treatment even in patients that ultimately attain a sustained virologic response.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008421","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T18:55:33Z","timestamp":1604602533000},"page":"e1008421","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mathematical modeling of hepatitis C RNA replication, exosome secretion and virus release"],"prefix":"10.1371","volume":"16","author":[{"given":"Carolin","family":"Zitzmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2359-2294","authenticated-orcid":true,"given":"Lars","family":"Kaderali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-0002","authenticated-orcid":true,"given":"Alan S.","family":"Perelson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2020,11,5]]},"reference":[{"key":"pcbi.1008421.ref001","author":"World Health Organization","year":"2018"},{"key":"pcbi.1008421.ref002","first-page":"140","author":"World Health Organization","year":"2016"},{"key":"pcbi.1008421.ref003","doi-asserted-by":"crossref","first-page":"32","DOI":"10.5501\/wjv.v2.i2.32","article-title":"Architecture and biogenesis of plus-strand RNA virus replication factories","volume":"2","author":"D Paul","year":"2013","journal-title":"World J Virol"},{"key":"pcbi.1008421.ref004","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.chom.2014.10.008","article-title":"Hepatitis C virus RNA replication and assembly: Living on the fat of the land","author":"D Paul","year":"2014","journal-title":"Cell Host and Microbe"},{"key":"pcbi.1008421.ref005","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/nm.3248","article-title":"Understanding the hepatitis C virus life cycle paves the way for highly effective therapies","volume":"19","author":"TKH Scheel","year":"2013","journal-title":"Nat Med"},{"key":"pcbi.1008421.ref006","doi-asserted-by":"crossref","first-page":"5907","DOI":"10.1128\/JVI.03404-13","article-title":"Dengue virus- and hepatitis C virus-induced replication","volume":"88","author":"L Chatel-Chaix","year":"2014","journal-title":"J Virol"},{"key":"pcbi.1008421.ref007","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.3748\/wjg.v22.i4.1477","article-title":"Host restriction factors for hepatitis C virus","volume":"22","author":"L-Y Zhou","year":"2016","journal-title":"World J Gastroenterol"},{"key":"pcbi.1008421.ref008","doi-asserted-by":"crossref","first-page":"12884","DOI":"10.1073\/pnas.0704894104","article-title":"Cellular cofactors affecting hepatitis C virus infection and replication","volume":"104","author":"G Randall","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1008421.ref009","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nrmicro.2017.60","article-title":"Viral effects on the content and function of extracellular vesicles","volume":"15","author":"N Raab-Traub","year":"2017","journal-title":"Nat Rev Microbiol"},{"key":"pcbi.1008421.ref010","first-page":"940","article-title":"Exosomes: Current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. 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Clausznitzer","year":"2015","journal-title":"Virus Res"},{"key":"pcbi.1008421.ref054","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/j.chom.2012.08.010","article-title":"Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity","volume":"12","author":"M Dreux","year":"2012","journal-title":"Cell Host Microbe"},{"key":"pcbi.1008421.ref055","doi-asserted-by":"crossref","first-page":"e1001058","DOI":"10.1371\/journal.pcbi.1001058","article-title":"Stochastic theory of early viral infection: Continuous versus burst production of virions","volume":"7","author":"JE Pearson","year":"2011","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1008421.ref056","doi-asserted-by":"crossref","first-page":"13594","DOI":"10.1128\/JVI.79.21.13594-13605.2005","article-title":"Quantitative analysis of the hepatitis C virus replication complex","volume":"79","author":"D Quinkert","year":"2005","journal-title":"J Virol"},{"key":"pcbi.1008421.ref057","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.tim.2010.11.005","article-title":"Assembly of infectious hepatitis C virus particles","volume":"19","author":"R Bartenschlager","year":"2011","journal-title":"Trends Microbiol"},{"key":"pcbi.1008421.ref058","doi-asserted-by":"crossref","first-page":"9505","DOI":"10.1073\/pnas.1307527110","article-title":"Ultrastructural analysis of hepatitis C virus particles","volume":"110","author":"MT Catanese","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1008421.ref059","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.jhep.2019.03.006","article-title":"Syntenin regulates hepatitis C virus sensitivity to neutralizing antibody by promoting E2 secretion through exosomes","volume":"71","author":"L Deng","year":"2019","journal-title":"J 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Heldt","year":"2012","journal-title":"J Virol"},{"key":"pcbi.1008421.ref063","doi-asserted-by":"crossref","first-page":"e1000035","DOI":"10.1371\/journal.ppat.1000035","article-title":"Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly","volume":"4","author":"N Appel","year":"2008","journal-title":"PLoS Pathog"},{"key":"pcbi.1008421.ref064","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.jhep.2012.09.022","article-title":"Host-targeting agents for prevention and treatment of chronic hepatitis C-Perspectives and challenges","volume":"58","author":"MB Zeisel","year":"2013","journal-title":"J Hepatol"},{"key":"pcbi.1008421.ref065","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1128\/MMBR.00063-15","article-title":"Extracellular vesicles exploit viral entry routes for cargo delivery","volume":"80","author":"HM van Dongen","year":"2016","journal-title":"Microbiol Mol Biol 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