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To effectively reduce the prevalence of HCV infection and associated diseases, it is important to understand the intracellular dynamics of the viral life cycle. Here, we present a detailed mathematical model that represents the full hepatitis C virus life cycle. It is the first full HCV model to be fit to acute intracellular infection data and the first to explore the functions of distinct viral proteins, probing multiple hypotheses of\n            <jats:italic>cis<\/jats:italic>\n            - and\n            <jats:italic>trans<\/jats:italic>\n            -acting mechanisms to provide insights for drug targeting. Model parameters were derived from the literature, experiments, and fitting to experimental intracellular viral RNA, extracellular viral titer, and HCV core and NS3 protein kinetic data from viral inoculation to steady state. Our model predicts higher rates for protein translation and polyprotein cleavage than previous replicon models and demonstrates that the processes of translation and synthesis of viral RNA have the most influence on the levels of the species we tracked in experiments. Overall, our experimental data and the resulting mathematical infection model reveal information about the regulation of core protein during infection, produce specific insights into the roles of the viral core, NS5A, and NS5B proteins, and demonstrate the sensitivities of viral proteins and RNA to distinct reactions within the life cycle.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            We have designed a model for the full life cycle of hepatitis C virus. Past efforts have largely focused on modeling hepatitis C virus replicon systems, in which transfected subgenomic HCV RNA maintains autonomous replication in the absence of virion production or spread. We started with the general structure of these previous replicon models and expanded it to create a model that incorporates the full virus life cycle as well as additional intracellular mechanistic detail. We compared several different hypotheses that have been proposed for different parts of the life cycle and applied the corresponding model variations to infection data to determine which hypotheses are most consistent with the empirical kinetic data. Because the infection data we have collected for this study are a more physiologically relevant representation of a viral life cycle than data obtained from a replicon system, our model can make more accurate predictions about clinical hepatitis C virus infections.\n          <\/jats:p>","DOI":"10.1128\/jvi.02098-17","type":"journal-article","created":{"date-parts":[[2018,3,22]],"date-time":"2018-03-22T09:38:42Z","timestamp":1521711522000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":31,"title":["Intracellular Hepatitis C Virus Modeling Predicts Infection Dynamics and Viral Protein Mechanisms"],"prefix":"10.1128","volume":"92","author":[{"given":"Thomas R.","family":"Aunins","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Marsh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gitanjali","family":"Subramanya","sequence":"additional","affiliation":[{"name":"Program for Experimental &amp; Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan L.","family":"Uprichard","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, USA"},{"name":"Program for Experimental &amp; Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-0002","authenticated-orcid":false,"given":"Alan S.","family":"Perelson","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anushree","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, Colorado, USA"},{"name":"BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Global hepatitis report","author":"World Health Organization","year":"2017","unstructured":"World Health Organization. 2017. 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