Building a mechanistic mathematical model of hepatitis C virus entry

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 virus 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. Author summary Hepatitis C virus affects approximately 70 million people worldwide, resulting in a significant impact on human health. The virus initiates infection through a complex set of interactions with proteins on the surface of human cells. Here we combine experimental approaches with a new mathematical model to study the process of viral entry. Our model is successful in capturing the behaviour of experiments, which show how changes in the amount of the human proteins CD81 and SR-B1 expressed by a cell alter the probability of a virus getting into a cell. Our model suggests that more than 10 CD81 receptors are needed to gain entry into a cell, and shows that viral entry is a difficult task, with many viruses failing at different stages of the entry process. Our model sets out a basis for further quantitative research into the process of HCV viral entry.