Intracellular hepatitis C modeling predicts infection dynamics and viral protein mechanisms Journal Article

Authors: Aunins, T. R.; Marsh, K. A.; Subramanya, G.; Uprichard, S. L.; Perelson, A. S.; Chatterjee, A.
Article Title: Intracellular hepatitis C modeling predicts infection dynamics and viral protein mechanisms
Abstract: Hepatitis C virus infection is a global health problem, with nearly 2 million new infections occurring every year and up to 85% of these becoming chronic infections that pose serious long-term health risks. To effectively reduce the prevalence of HCV infection and associated diseases, it is important to understand the intracellular dynamics of the viral lifecycle. Here, we present a detailed mathematical model that represents the full hepatitis C lifecycle. 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 cis- and trans-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 faster 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 lifecycle.IMPORTANCE We have designed a model for the full lifecycle of hepatitis C virus. Past efforts have largely focused on modeling hepatitis C 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 to create a model that incorporates the full virus lifecycle as well as additional intracellular mechanistic detail. We compared several different hypotheses that have been proposed for different parts of the lifecycle 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 is a more physiologically relevant representation of a viral lifecycle than data obtained from a replicon system, our model can make more accurate predictions about clinical hepatitis C infections.
Journal Title: Journal of virology
ISSN: 1098-5514; 0022-538X
Publisher: American Society for Microbiology  
Journal Place: United States
Date Published: 2018
Language: eng
Notes: LR: 20180322; CI: Copyright (c) 2018; JID: 0113724; 2018/03/23 06:00 [entrez]; 2018/03/23 06:00 [pubmed]; 2018/03/23 06:00 [medline]; aheadofprint