The HEV capsid through a dynamic lens: parallels and divergence from caliciviruses.

The hepatitis E virus (HEV) capsid protein, pORF2, mediates virion assembly, attachment and entry, yet the molecular mechanisms underlying these processes remain poorly defined. Structural studies have provided high-resolution views of pORF2 virus-like particles, revealing an architecture like that of the calicivirus VP1. However, while a paradigm has been established for calicivirus capsid dynamicity - environmentally triggered transitions that regulate receptor engagement, uncoating and immune evasion - comparable conformational plasticity has not yet been explored for HEV. At the same time, efforts to map pORF2 interactions with host factors have yielded several candidate attachment and entry molecules, but no definitive receptor. This review summarises the current knowledge of the structure, forms and host interactions of pORF2, contrasting it with the extensive body of work that has revealed the dynamic behaviour of the calicivirus capsid. This 'dynamic capsid lens' view of HEV may inspire new approaches to unresolved aspects of HEV entry biology. These include how pORF2 engages with host factors, how quasi-enveloped and non-enveloped particles differ functionally, and whether environmental cues encountered during gut-to-liver transit affect capsid conformation. To determine whether HEV, like its calicivirus relatives, exploits capsid dynamicity to establish infection, it will be key to integrate structural, biophysical and cell-based approaches.