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Hepatitis A virus and the origins of picornaviruses

Nature volume 517, pages 8588 (01 January 2015) | Download Citation



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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The coordinates and structure factors for the full and empty particles have been deposited with the RCSB Protein Data Bank under accession codes 4QPI and 4QPG, respectively.


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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.

Author information

Author notes

    • Xiangxi Wang
    • , Jingshan Ren
    •  & Qiang Gao

    These authors contributed equally to this work.


  1. National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China

    • Xiangxi Wang
    • , Qiang Gao
    • , Yao Sun
    • , Xuemei Li
    •  & Zihe Rao
  2. Division of Structural Biology, University of Oxford, The Henry Wellcome Building for Genomic Medicine, Headington, Oxford OX3 7BN, UK

    • Jingshan Ren
    • , David I. Stuart
    •  & Elizabeth E. Fry
  3. Sinovac Biotech Co., Ltd, Beijing 100085, China

    • Qiang Gao
    •  & Weidong Yin
  4. National Institutes for Food and Drug Control, No. 2, TiantanXili, Beijing 100050, China

    • Zhongyu Hu
    •  & Junzhi Wang
  5. Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK

    • David J. Rowlands
  6. Diamond Light Sources, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK

    • David I. Stuart
  7. Laboratory of Structural Biology, School of Medicine, Tsinghua University, Beijing 100084, China

    • Zihe Rao
  8. State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300071, China

    • Zihe Rao


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Q.G., J.W., Z.H. and W.Y. prepared samples. X.W., J.R., Q.G., X.L., Y.S., E.E.F. and D.I.S. performed research, J.R., X.W., E.E.F. and D.I.S. analysed data and with D.J.R. and Z.R. wrote the manuscript, in discussion with J.W. and Z.H.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Junzhi Wang or David I. Stuart or Zihe Rao.

Extended data

Supplementary information


  1. 1.

    In-situ crystal analysis: movement on exposure to X-rays.

    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.

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