Abstract
Viruses are obligatory parasites that take advantage of intracellular niches to replicate. During infection, their genomes are carried in capsids across the membranes of host cells to sites of virion production by exploiting cellular behaviour and resources to guide and achieve all aspects of delivery and the downstream virus manufacturing process. Successful entry hinges on execution of a precisely tuned viral uncoating program where incoming capsids disassemble in consecutive steps to ensure that genomes are released at the right time, and in the right place for replication to occur. Each step of disassembly is cell-assisted, involving individual pathways that transmit signals to regulate discrete functions, but at the same time, these signalling pathways are organized into larger networks, which communicate back and forth in complex ways in response to the presence of virus. In this review, we consider the elegant strategy by which adenoviruses (AdVs) target and navigate cellular networks to initiate the production of progeny virions. There are many remarkable aspects about the AdV entry program; for example, the virus gains targeted control of a large well-defined local network neighbourhood by coupling several interacting processes (including endocytosis, autophagy and microtubule trafficking) around a collective reference state centred on the interactional topology and multifunctional nature of protein VI. Understanding the network targeting activity of protein VI, as well as other built-in mechanisms that allow AdV particles to be efficient at navigating the subsystems of the cell, can be used to improve viral vectors, but also has potential to be incorporated for use in entirely novel delivery systems.