Building a mechanistic mathematical model of hepatitis C virus entry.

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dc.creatorKalemera, Mphatso
dc.creatorMincheva, Dilyana
dc.creatorGrove, Joe
dc.creatorIllingworth, Christopher JR
dc.date2019-03-05T00:30:56Z
dc.date2019-03-05T00:30:56Z
dc.date2019-03
dc.date.accessioned2026-08-03T01:41:16Z
dc.descriptionThe 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.
dc.descriptionWellcome, Royal Society, Newton Trust
dc.formatElectronic-eCollection
dc.formatapplication/vnd.openxmlformats-officedocument.wordprocessingml.document
dc.formatapplication/pdf
dc.identifier1553-734X
dc.identifierhttps://www.repository.cam.ac.uk/handle/1810/290178
dc.identifier10.17863/CAM.37406
dc.identifier1553-7358
dc.identifier.urihttps://repo.dare.co.zw/handle/123456789/157869
dc.languageeng
dc.languageeng
dc.publisherPublic Library of Science (PLoS)
dc.publisherhttps://doi.org/10.1371/journal.pcbi.1006905
dc.subjectCell Line, Tumor
dc.subjectComputational Biology
dc.subjectHepacivirus
dc.subjectHepatitis C
dc.subjectHost-Pathogen Interactions
dc.subjectHumans
dc.subjectModels, Molecular
dc.subjectReceptors, Virus
dc.subjectVirus Internalization
dc.titleBuilding a mechanistic mathematical model of hepatitis C virus entry.
dc.typeArticle

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