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.
Highlights
Viral particles at first glance may appear as little more than a genome enclosed in a simple protein cage; often times highly symmetrical in nature and in some instances wrapped in a lipid bilayer
In the case of AdV, the uncoating program ensures timely release of a multifunctional inner capsid protein that has membrane lytic properties, protein VI, which is capable of rupturing flows on the endocytic network before the 6 virus can be directed to the lysosome for degradation [87,88,89]
The nuclear envelope (NE) serves as a physical bilayer partition, and as an information-processing centre for regulated exchange of matter between the nucleus and cytoplasm. The latter function is made possible by incorporation of dynamic channel-forming nuclear pore complexes (NPCs), each consisting of hundreds of proteins called nucleoporins (Nups), which include both structural Nups that build the scaffolding structure of the pore and phenylalanine-glycine-rich (FG-rich) intrinsically disordered Nups that emanate as fibrils into the cytoplasm and line the central channel to provide a selective passageway for receptormediated active transport [114,115]
Summary
Viral particles at first glance may appear as little more than a genome enclosed in a simple protein cage; often times highly symmetrical in nature and in some instances wrapped in a lipid bilayer. Even more challenging is the task of achieving a structural understanding of cell-mediated disassembly of virus particles from the metastable state to genome release [4]. The technical ability to correlate changes in viral structure with discrete steps in cell entry has largely been beyond reach, and even trying to simulate the process in a computer is too difficult due to the context, size and time scale of capsid uncoating. We discuss how AdV movement and disassembly occurs in time, through space, and by some kind of microenvironmental force, effort or energy, so that incoming viral genomes are released at the appropriate location for replication
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