Hepatitis A virus (HAV) remains enigmatic, despite 1.4 million cases worldwide annually1. It differs radically from other picornaviruses, existing in an enveloped form2 and being unusually stable, both genetically and physically3, but has proved difficult to study. Here we report high-resolution X-ray structures for the mature virus and the empty particle. The structures of the two particles are indistinguishable, apart from some disorder on the inside of the empty particle. The full virus contains the small viral protein VP4, whereas the empty particle harbours only the uncleaved precursor, VP0. The smooth particle surface is devoid of depressions that might correspond to receptor-binding sites. Peptide scanning data extend the previously reported VP3 antigenic site4, while structure-based predictions5 suggest further epitopes. HAV contains no pocket factor and can withstand remarkably high temperature and low pH, and empty particles are even more robust than full particles. The virus probably uncoats via a novel mechanism, being assembled differently to other picornaviruses. It utilizes a VP2 ‘domain swap’ characteristic of insect picorna-like viruses6,7, and structure-based phylogenetic analysis places HAV between typical picornaviruses and the insect viruses. The enigmatic properties of HAV may reflect its position as a link between ‘modern’ picornaviruses and the more ‘primitive’ precursor insect viruses; for instance, HAV retains the ability to move from cell-to-cell by transcytosis8,9.
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This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, grant no. XDB08020200, the Ministry of Science and Technology 973 Project (grant no. 2014CB542800), the National Major Project of Infectious Disease (2012ZX10004701) and National Science Foundation grant 81330036. D.I.S. and E.E.F. are supported by the UK Medical Research Council (grant G1000099) and J.R. by the Wellcome Trust. This work is a contribution from the Instruct Centre, Oxford. Administrative support was provided by the Wellcome Trust (075491/Z/04). We thank J. Johnson and A. Routh for supplying CrPV, and S. Lemon and K. McKnight for discussions.
Extended data figures
Extended data tables
A trapezoidal plate-shaped crystal of HAV (100×100×5 μm, thin axis parallel to the X-ray beam), in mother liquor containing 30% MPD, was exposed for 0.1 s to full beam (∼1012 photons s-1) at I24, Diamond at room temperature. The real-time video (viewed co-axial to the X-ray beam) shows the crystal darting upwards and left away from the beam (marked by white cross-hairs) once the exposure begins (at 3 s) before returning to its starting position. The pale grey scale bar bottom right shows 50 μm horizontally.
About this article
Nature Microbiology (2016)