Virus adaptation to heparan sulfate comes with capsid stability tradeoff
Summary
Because of high mutation rates, viruses constantly adapt to new environments. When propagated in cell lines, certain viruses acquire positively charged amino acids on their surface proteins, enabling them to utilize negatively charged heparan sulfate (HS) as an attachment receptor. In this study, the authors used enterovirus A71 (EV-A71) as the model and demonstrated that, unlike the parental MP4 variant, the cell-adapted strong HS-binder MP4-97R/167 G does not require acidification for uncoating and releases its genome in the neutral or weakly acidic environment of early endosomes. They experimentally confirmed that this pH-independent entry is not associated with the use of HS as an attachment receptor but rather with compromised capsid stability. They then extended these findings to another HS-dependent strain. In summary, their data indicate that the acquisition of capsid mutations conferring affinity for HS comes together with decreased capsid stability and allows EV-A71 to enter the cell via a pH-independent pathway. This pH-independent entry mechanism boosts viral replication in cell lines but may prove deleterious in vivo, especially for enteric viruses crossing the acidic gastric environment before reaching their primary replication site, the intestine. This study thus provides new insight into the mechanisms underlying the in vivo attenuation of HS-binding EV-A71 strains. Not only are these viruses hindered in tissues rich in HS due to viral trapping, as generally accepted, but this research reveals that their diminished capsid stability further contributes to attenuation in vivo. This underscores the complex relationship between HS-binding, capsid stability, and viral fitness, where increased replication in cell lines coincides with attenuation in harsh in vivo environments like the gastrointestinal tract.
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WHY IS IT IMPORTANT?
Researchers studied how the enterovirus A71 (EV-A71), which can cause hand, foot, and mouth disease, adapts to lab conditions. Mutations allow the virus to attach to a cell-surface molecule called heparan sulfate (HS), helping it replicate faster in cells. However, these mutations make the virus less stable and less able to survive harsh environments, like the acidic stomach.
This discovery explains why some lab-adapted viruses are less effective at causing infections in living organisms and provides insights for future antiviral strategies. Additionally, it enhances our understanding of the pathogenesis of EV-A71 clinical strains, which utilize HS as an attachment receptor during human infection
20 Jan 2025