Network controllability: viruses are driver agents in dynamic molecular systems

Abstract

In recent years control theory has been applied to biological systems with the aim of identifying the minimum set of molecular interactions that can drive the network to a required state. However in an intra-cellular network it is unclear what control means. To address this limitation we use viral infection, specifically HIV-1 and HCV, as a paradigm to model control of an infected cell. Using a large human signalling network comprised of over 6000 human proteins and more than 34000 directed interactions, we compared two dynamic states: normal/uninfected and infected. Our network controllability analysis demonstrates how a virus efficiently brings the dynamic host system into its control by mostly targeting existing critical control nodes, requiring fewer nodes than in the uninfected network. The driver nodes used by the virus are distributed throughout the pathways in specific locations enabling effective control of the cell via the high control centrality of the viral and targeted host nodes. Furthermore, this viral infection of the human system permits discrimination between available network-control models, and demonstrates the minimum-dominating set (MDS) method better accounts for how biological information and signals are transferred than the maximum matching (MM) method as it identified most of the HIV-1 proteins as critical driver nodes and goes beyond identifying receptors as the only critical driver nodes. This is because MDS, unlike MM, accounts for the inherent non-linearity of signalling pathways. Our results demonstrate control-theory gives a more complete and dynamic understanding of the viral hijack mechanism when compared with previous analyses limited to static single-state networks.