Hepatitis A virus and the origins of picornaviruses

Abstract

Hepatitis A virus is a picornavirus that causes significant morbidity but remains poorly understood; this paper now provides high-resolution crystal structures of both the mature and the empty hepatitis A virus particle, which show that the three-dimensional structure resembles insect picorna-like viruses. Hepatitis A virus is a picornavirus that causes significant mortality, but despite the availability of vaccines, the mechanism by which virus infection is established remains poorly understood. Xiangxi Wang et al. provide high-resolution crystal structures of both the mature and the empty hepatitis A virus particle that explain some of the virus's unusual properties such as its resistance to high temperatures, and suggest a novel entry mechanism. The three-dimensional structure resembles insect picorna-like viruses, implying that it is an evolutionary link between 'modern' picornaviruses and the more 'primitive' precursor insect viruses. 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.