Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution

  • Nature volume 517, pages 505508 (22 January 2015)
  • doi:10.1038/nature13838
  • Download Citation


Human immunodeficiency virus type 1 (HIV-1) assembly proceeds in two stages. First, the 55 kilodalton viral Gag polyprotein assembles into a hexameric protein lattice at the plasma membrane of the infected cell, inducing budding and release of an immature particle. Second, Gag is cleaved by the viral protease, leading to internal rearrangement of the virus into the mature, infectious form1. Immature and mature HIV-1 particles are heterogeneous in size and morphology, preventing high-resolution analysis of their protein arrangement in situ by conventional structural biology methods. Here we apply cryo-electron tomography and sub-tomogram averaging methods to resolve the structure of the capsid lattice within intact immature HIV-1 particles at subnanometre resolution, allowing unambiguous positioning of all α-helices. The resulting model reveals tertiary and quaternary structural interactions that mediate HIV-1 assembly. Strikingly, these interactions differ from those predicted by the current model based on in vitro-assembled arrays of Gag-derived proteins from Mason–Pfizer monkey virus2. To validate this difference, we solve the structure of the capsid lattice within intact immature Mason–Pfizer monkey virus particles. Comparison with the immature HIV-1 structure reveals that retroviral capsid proteins, while having conserved tertiary structures, adopt different quaternary arrangements during virus assembly. The approach demonstrated here should be applicable to determine structures of other proteins at subnanometre resolution within heterogeneous environments.

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Electron Microscopy Data Bank

Protein Data Bank

Data deposits

Cryo-electron microscopy structures and a representative tomogram have been deposited in the Electron Microscopy Data Bank under accession numbers EMD-2706, EMD-2707 and EMD-2708, and the fitted HIV atomic model in the PDB under accession number 4USN.


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This study was supported by Deutsche Forschungsgemeinschaft grants BR 3635/2-1 to J.A.G.B., KR 906/7-1 to H.-G.K. and by Grant Agency of the Czech Republic 14-15326S to M.R. The Briggs laboratory acknowledges financial support from the European Molecular Biology Laboratory and from the Chica und Heinz Schaller Stiftung. We thank B. Glass, M. Anders and S. Mattei for preparation of samples, and R. Hadravova, K. H. Bui, F. Thommen, M. Schorb, S. Dodonova, S. Glatt, P. Ulbrich and T. Bharat for technical support and/or discussion. This study was technically supported by the European Molecular Biology Laboratory IT services unit.

Author information


  1. Structural and Computational Biology Unit, European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany

    • Florian K. M. Schur
    • , Wim J. H. Hagen
    •  & John A. G. Briggs
  2. Molecular Medicine Partnership Unit, European Molecular Biology Laboratory/Universitätsklinikum Heidelberg, Heidelberg, Germany

    • Florian K. M. Schur
    • , Barbara Müller
    • , Hans-Georg Kräusslich
    •  & John A. G. Briggs
  3. Institute of Organic Chemistry and Biochemistry (IOCB), Academy of Sciences of the Czech Republic, v.v.i., IOCB & Gilead Research Center, Flemingovo nám. 2, 166 10 Prague, Czech Republic

    • Michaela Rumlová
  4. Department of Biotechnology, Institute of Chemical Technology, Prague, Technická 5, 166 28, Prague, Czech Republic

    • Michaela Rumlová
  5. Department of Biochemistry and Microbiology, Institute of Chemical Technology, Prague, Technická 5, 166 28, Prague, Czech Republic

    • Tomáš Ruml
  6. Department of Infectious Diseases, Virology, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany

    • Barbara Müller
    •  & Hans-Georg Kräusslich


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F.K.M.S., M.R., T.R., B.M., H.-G.K. and J.A.G.B. designed and interpreted experiments. F.K.M.S. and W.J.H.H. collected data, F.K.M.S. performed image processing, and F.K.M.S. and J.A.G.B. analysed data. F.K.M.S. and J.A.G.B. wrote the manuscript with support from all authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to John A. G. Briggs.

Extended data

Supplementary information


  1. 1.

    3D visualization of the structure presented in Figure 1b‐d

    3D visualization of the structure presented in Figure 1b‐d.

  2. 2.

    A tour through the structure presented in Figure 1b-d highlighting key structural interfaces and features discussed in this study

    A tour through the structure presented in Figure 1b-d highlighting key structural interfaces and features discussed in this study.

  3. 3.

    A comparison between the immature and mature HIV capsid lattice as generated with the “Morph Conformations” option in Chimera

    The starting model was the flexible fit generated in this study propagated out into 7 hexamers. The mature model is PDB 3J34. Additionally, the comparison of one immature dimer with its mature form is shown in an orthogonal view. Note that in vivo, maturation does not proceed as a morph and must require at least partial disassembly of the CA lattice.


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