Building a mechanistic mathematical model of hepatitis C virus entry
Fig 5
Building a mechanistic model of HCV entry.
A. Following attachment HCV particles must engage and accumulate CD81 to proceed to entry. B. To model this process we must consider a HCV particle that has an unknown (Ne) number of E2 molecules. C. We modelled E2 receptor engagement to occur via two routes: 1. prior engagement of SR-B1 enhances E2 interaction with CD81 2. acquisition of CD81 via intrinsic binding, with no prior involvement of other receptors. The molecular models are drawn to scale and are based on published crystal structures (E2 PDB:6MEJ;CD81 PDB:5TCX; SR-B1 homology model based on PDB:4F7B [56,63,64]) D. A parameterised mathematical framework of receptor engagement. Each box represents the receptor engagement state of cell-attached viruses (M), where the values in parentheses denote receptor number. For example, M(0,0) represents viruses that have attached but have not yet engaged either receptor, M(1,0) represents viruses that have acquired one molecule of CD81 and M(0,1) are viruses with one molecule of SR-B1. The steps in this process have been parameterised to include the availability of receptor (determined by experimental data) and the rate of engagement (estimated by modelling). They have also been scaled relative to the number of available E2 molecules (Ne). For clarity, parameterised steps are also shown in C. E. A matrix model of HCV receptor accumulation. To achieve productive infection (I) virus particles must move laterally, acquiring CD81, this is achieved via the routes defined in D. The dimensions of this matrix represent the stoichiometry of receptor engagement (i.e. how many molecules of CD81 are required for entry), we investigated this through the modelling process. There are two additional parameters in the model, e integrates all downstream events in the virus life cycle leading to productive infection, whereas d is the rate of spontaneous virus inactivation, or ‘death’.