A tradeoff between enterovirus A71 particle stability and cell entry

Abstract

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 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.

Enterovirus A71 adaptation to heparan sulfate comes with capsid stability tradeoff

“…Given that these two HSdependent variants share the characteristic of having incorporated a less acidic amino acid within the VP1 capsid protein, we hypothesized that an increase in positive charges within the capsid not only enhances affinity for HS but also alters capsid stability, consequently impacting the virus entry mechanism. In the same line, a thermostable EV-A71 variant (VP1-K162E, change of a basic to an acidic residue) isolated from serial passages at higher temperatures was shown to be less efficient at uncoating with poorer cell infectivity but more virulent in mice 47 . Interestingly, this variant showed a more expanded conformation compared to the original non-mutated virus 47 .…”

“…In the same line, a thermostable EV-A71 variant (VP1-K162E, change of a basic to an acidic residue) isolated from serial passages at higher temperatures was shown to be less efficient at uncoating with poorer cell infectivity but more virulent in mice 47 . Interestingly, this variant showed a more expanded conformation compared to the original non-mutated virus 47 . While the thermostable variant showed no difference in binding to SCARB2 receptor, the binding affinity to heparin was greatly reduced, an observation consistent with what we noticed for MP4.…”

Mechanism of enterovirus VP0 maturation cleavage based on the structure of a stabilised assembly intermediate

“…Mature virions attach to cells via cell surface receptors/co-receptors and the genome is released following conformational changes induced by receptor interaction and/or local environmental changes (pH and ionic changes in endosomes etc.) [1][2][3][4][5][6][7].…”