Building a mechanistic mathematical model of hepatitis C virus entry

Kalemera, M., Mincheva, D., Grove, J. and Illingworth, C. J. R. (2019) Building a mechanistic mathematical model of hepatitis C virus entry. PLoS Computational Biology, 15(3), e1006905. (doi: 10.1371/journal.pcbi.1006905) (PMID:30883541) (PMCID:PMC6445459)

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The mechanism by which hepatitis C virus (HCV) gains entry into cells is a complex one, involving a broad range of host proteins. Entry is a critical phase of the viral lifecycle, and a potential target for therapeutic or vaccine-mediated intervention. However, the mechanics of HCV entry remain poorly understood. Here we describe a novel computational model of viral entry, encompassing the relationship between HCV and the key host receptors CD81 and SR-B1. We conduct experiments to thoroughly quantify the influence of an increase or decrease in receptor availability upon the extent of viral entry. We use these data to build and parameterise a mathematical model, which we then validate by further experiments. Our results are consistent with sequential HCV-receptor interactions, whereby initial interaction between the HCV E2 glycoprotein and SR-B1 facilitates the accumulation CD81 receptors, leading to viral entry. However, we also demonstrate that a small minority of viruses can achieve entry in the absence of SR-B1. Our model estimates the impact of the different obstacles that viruses must surmount to achieve entry; among virus particles attaching to the cell surface, around one third of viruses accumulate sufficient CD81 receptors, of which 4–8% then complete the subsequent steps to achieve productive infection. Furthermore, we make estimates of receptor stoichiometry; in excess of 10 receptors are likely to be required to achieve viral entry. Our model provides a tool to investigate the entry characteristics of HCV variants and outlines a framework for future quantitative studies of the multi-receptor dynamics of HCV entry.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Illingworth, Dr Chris
Creator Roles:
Illingworth, C. J.R.Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing
Authors: Kalemera, M., Mincheva, D., Grove, J., and Illingworth, C. J. R.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Journal Name:PLoS Computational Biology
Publisher:Public Library of Science
ISSN (Online):1553-7358
Published Online:18 March 2019
Copyright Holders:Copyright © 2019 Kalemera et al.
First Published:First published in PLoS Computational Biology 15(3): e1006905
Publisher Policy:Reproduced under a Creative Commons License

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