A tradeoff between enterovirus A71 particle stability and cell entry

AbstractA 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 perturbed this equilibrium in a non-enveloped virus, enterovirus A71 to determine its structural basis. We isolated a single-point mutation variant with increased particle thermotolerance and decreased efficiency of cell entry. Using cryo-electron microscopy and molecular dynamics simulations, we determined that the thermostable native particles have acquired an expanded conformation that results in a significant increase in protein dynamics. Examining the uncoating intermediate states of the thermostable variant suggests a pathway, where the lipid pocket factor is released first, followed by internal VP4 and finally the viral RNA.