A tradeoff between enterovirus A71 particle stability and cell entry

A central role of viral capsids is to protect the viral genome from the harsh extracellular environment while facilitating initiation of infection when the virus encounters a target cell. Viruses are thought to have evolved an optimal equilibrium between particle stability and efficiency of cell entry. In this study, we genetically perturb this equilibrium in a non-enveloped virus, enterovirus A71 to determine its structural basis. We isolate a single-point mutation variant with increased particle thermotolerance and decreased efficiency of cell entry. Using cryo-electron microscopy and molecular dynamics simulations, we determine that the thermostable native particles have acquired an expanded conformation that results in a significant increase in protein dynamics. Examining the intermediate states of the thermostable variant reveals a potential pathway for uncoating. We propose a sequential release of the lipid pocket factor, followed by internal VP4 and ultimately the viral RNA.