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

Nature volume 517, pages 505–508 (2015)Cite this article

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Abstract

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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Figure 1: Structure of the CA-SP1 lattice within immature HIV-1.
Figure 2: Interactions stabilizing the immature HIV-1 capsid lattice.
Figure 3: Structure of the capsid lattice within immature M-PMV (D26N) particles.
Figure 4: Comparison of the CA arrangement in immature and mature retroviruses.

Accession codes

Primary accessions

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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Acknowledgements

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

Authors and Affiliations

  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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  1. Florian K. M. Schur
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Contributions

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.

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Correspondence to John A. G. Briggs.

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Extended data figures and tables

Extended Data Figure 1 Characterization of virus preparations used in this study.

Samples of Optiprep gradient (OP)-purified particles were separated by SDS–polyacrylamide gel electrophoresis. Proteins were visualized by silver staining or immunoblot, respectively, as indicated. For immunoblot analysis, proteins were transferred to nitrocellulose membranes by semi-dry blotting. Membranes were probed with polyclonal antiserum raised against recombinant HIV-1 CA (a) or M-PMV NC (c), respectively. Bound antibodies were visualized by quantitative immunodetection on a LiCor Odyssey imager, using secondary antibodies and protocols according to the manufacturer’s instructions. a, HIV-1 particles prepared in the presence of 5 µM APV. Note that residual processing of Gag has occurred due to incomplete protease inhibition. The main additional Gag product (∼50 kDa) corresponds to Gag lacking the C-terminal p6-region; we have previously shown that cleavages downstream of SP1 do not disrupt the immature Gag lattice41. b, Immature HIV-1 particles prepared from cells transfected with pNL4-3 (PR-, D25A) compared with a standard of purified Gag. Note that Gag is completely uncleaved in this case. c, Immature protease defective M-PMV particles purified from cells transfected with plasmid pSHRM15 (D26N). Positions of molecular mass standards (in kilodaltons) are indicated.

Extended Data Figure 2 Cryo-electron tomography and subtomogram averaging reconstruction of the immature HIV-1 lattice.

a, Within pleiotropic HIV particles the polyprotein Gag forms incomplete hexameric lattices of heterogeneous shapes. Tomographic slices of two representative viruses are shown. Underneath the membrane, ordered protein density corresponding to capsid can be seen. In the middle and lower panels, virus particles are displayed with their respective output lattice maps as derived from subtomogram averaging. The colour of the hexagons denotes the cross-correlation coefficient (CCC) of the alignment ranging from red (low CCC (0.04)) to green (high CCC (0.19)). In the lower panel, the view has been tilted to reveal regions with no lattice. Areas with no protein density underneath the membrane are devoid of a hexameric lattice. Scale bar, 50 nm. b, FSC between two half-data sets (each of which was independently aligned and averaged starting from independent references) of immature HIV treated with APV (blue line) showing a resolution of 9.8/8.8 Å at the 0.5/0.143 criterion, respectively. The equivalent FSC for a lower-resolution structure of the protease defective HIV (D25A) sample (red line) shows a resolution of 12.6/10.9 Å at the 0.5/0.143 criterion. c, Central orthoslice through the final average of the protease-inhibitor-treated HIV reconstruction (no inverse B-factor was applied). Ordered density is only observed in the CA-SP1 region. The dashed rectangle indicates the region shown in d. d, Orthoslice through the CA-SP1 region in the final average of HIV-1 + APV (left, corrected with an inverse B-factor of −1200 Å2), the same structure filtered to 13 Å (middle) and of the protease defective HIV-1 (D25A) preparation filtered to 13 Å (right), indicating that protease-inhibited and protease mutant structures have the same domain arrangement. The dashed lines indicate the positions of horizontal orthoslices in e and f. Scale bar, 50 Å.

Extended Data Figure 3 Molecular dynamics flexible fitting of high-resolution HIV-1 CA structures into the electron microscopy density.

a, The rigid body fit used as a starting model for flexible fitting superimposed onto the electron microscopy map. b–d, The final flexible fit superimposed onto the electron microscopy map viewed at three different isosurface thresholds. The flexible fitting resulted in only minor movements relative to the initial rigid-body fit, implying that individual CA domains do not undergo large changes in structure between the isolated and assembled protein domains. At lower isosurface thresholds, densities corresponding to the cyclophilin-A binding loop and the 7–8 linker can be seen (positions annotated in a). One of the positions at which CA-NTD and CA-CTD contact one another is marked by an arrow. Isosurface values are indicated in the figure (threshold value is σ away from the mean).

Extended Data Figure 4 Comparison of different retroviral CA-CTD dimer structures.

a–d, Comparison of different CA-CTD dimers aligned against the immature flexibly fitted HIV-1 CA-CTD dimer obtained in this study (orange). a, PDB 3DS2 (red, the crystal structure that most closely resembles the immature CA-CTD); b, the structure recently obtained by fitting a crystal dimer into in vitro-assembled HIV-1 tubes7 (pink); c, the immature M-PMV dimer based on a homology model fitted into the immature M-PMV electron microscopy density generated in this study (green); d, a mature HIV-1 CA-CTD dimer from PDB 3J34 (ref. 6) (light blue, chain A and f). The backbone root mean squared deviations between the superimposed structures are 6.8 Å (a), 3.2 Å (b), 6.4 Å (c) and 17.9 Å (d).

Extended Data Figure 5 Cryo-electron tomography and subtomogram averaging reconstruction of immature M-PMV (D26N) viruses.

a, Slices through two tomograms containing immature M-PMV (D26N) particles. Using subtomogram averaging, the position and the arrangement of the hexameric capsid lattice can be resolved (middle and lower panels). See Extended Data Fig. 2 for explanations. CCC values range from 0.05 to 0.14. Scale bar, 50 nm. b, FSC of the two independently aligned and averaged half-data sets of the M-PMV (D26N) sample. The resolution corresponds to 11.2 and 9.7 Å at the 0.5/0.143 criterion, respectively. c, Side view orthoslice through the final average of the protease defective M-PMV reconstruction (no inverse B-factor was applied). No ordered densities are observed except for the CA region. The dashed rectangle indicates the region shown in d. d, Orthoslice through the CA region in the final average corrected with a B-factor of −1,000 Å2. The dashed lines indicate the positions of horizontal orthoslices in e and f. Scale bar, 50 Å.

Extended Data Figure 6 Comparison of immature protease defective M-PMV (D26N) particles and M-PMV ΔPro CANC tubes.

a, An isosurface representation of the structure generated from M-PMV (D26N) virus particles, as presented in this study. The structure is shown from the outside of the virus (top), in a horizontal slice (middle) and from the inside of the virus (bottom). b, For comparison, equivalent views of the structure from in vitro-assembled M-PMV ΔPro CANC tubular arrays (EMD2089)2 are shown. Both structures have been filtered to 10 Å and the threshold was set to 2σ away from the mean. The additional density observed for the M-PMV ΔPro CANC tube structure (coloured red in the middle and bottom panel) is thought to be a nucleic acid structure that is ordered in the tubular arrays2. Scale bar, 25 Å.

Extended Data Figure 7 Structural conservation of retroviral CA domains.

Known atomic structures of CA-NTD and CA-CTD domains from the lentivirus13,14, α42,43, β40, γ44 and δ45,46 retrovirus families. The tertiary structure of CA domains is highly conserved between different retroviruses.

Extended Data Figure 8 Comparison of CA domain arrangements in immature M-PMV, immature HIV and mature HIV.

a, Two-dimensional schematic representations of immature M-PMV, immature HIV and mature HIV particles. Retroviruses bud from infected cells in an immature form. The Gag polyprotein is radially arranged underneath the host-derived plasma membrane (yellow) and includes the membrane associated matrix domain (MA, black), the bipartite capsid domain (CA, blue and red) and the nucleic-acid-bound nucleocapsid (NC, green). M-PMV possesses two additional domains positioned between MA and CA, termed pp24 and p12 (purple), leading to a bigger spatial separation of CA and MA compared with HIV. The viral protease cleaves the Gag polyprotein at defined positions, triggering maturation. This process leads to a rearrangement of the domains, giving rise to the mature, infectious virus. b–d, Schematic diagram representing the arrangement of the CA-NTD and CA-CTD domains within immature M-PMV and HIV and within mature HIV. CA-NTD and CA-CTD molecules are represented by cyan/blue- and orange/red-coloured solids, respectively. The solids are positioned at the exact positions and orientations at which the high-resolution structures fitted into the electron microscopy densities. For CA-NTD the N terminus and for CA-CTD the C terminus are represented as spherical extensions. The shown schematics were generated in UCSF Chimera by defining the translational and rotational matrix of each fitted CA domain, and applying it to the solid representations. b, Both CA-NTD (cyan/blue) and CA-CTD (orange/red) domains are shown; c, CA-NTD only; d, CA-CTD only.

Extended Data Table 1 Data processing statistics
Full size table

Supplementary information

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

3D visualization of the structure presented in Figure 1b‐d. (MOV 10399 kb)

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. (MOV 21598 kb)

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. (MOV 4862 kb)

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Schur, F., Hagen, W., Rumlová, M. et al. Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution. Nature 517, 505–508 (2015). https://doi.org/10.1038/nature13838

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