Intracellular “in silico microscopes” – fully 3D spatial Hepatitis C virus replication model simulations

Abstract

Virus pandemics and endemics cause enormous pain and economic, political, and social costs and turmoil. While the Covid19 pandemics induced obvious damages, the "silent" Hepatitis C virus (HCV) infection induced liver damages are the main reason for liver transplantations. HCV-generated virus genome replication factories are housed within virus-induced intracellular structures termed membranous webs (MW) which are derived from the Endoplasmatic Reticulum (ER). Up to now, very advanced experimental data such as highly spatially resolved fluorescence and electron-tomography data often do not enter computational HCV viral RNA (vRNA) cycle models. Based upon diffusion-reaction partial differential equation (PDE) models, we are developing fully 3D resolved “in silico microscopes” to mirror in vitro / in vivo experiments of the intracellular vRNA cycle dynamics. Our first models described the major components (vRNA, non-structural viral proteins - NSPs - and a host factor). The next steps incorporated additional parameters: Different aggregate states of vRNA and NSPs, and population dynamics inspired diffusion and reaction coefficients instead of multilinear ones. Our work in progress framework presently is merging effects restricted to 2D manifold surface grids (e.g. ER surface, NSP diffusion) with others occurring in 3D volume meshes (e.g. cytosol, host factor supply). We estimate and incorporate realistic parameters such as NSP diffusion constants. The simulations are performed upon experimental data based reconstructed cell geometries and help understanding the relation of form and function of virus replication. In the long run, our framework might help to facilitate the systematic development of efficient direct antiviral agents and vaccines.