Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution
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 form. 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 virus. 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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Although previous low-resolution structures showed a similar immature lattice spacing of 80 A and suggested a conserved CA-NTD arrangement, the arrangement of the CA-NTD domains was different in all three viruses when observed at higher resolution.
“Unexpectedly, although previous low-resolution structures had showed a similar immature lattice spacing of 80 A ˚ and suggested a conserved CA-NTD arrangement [33,34], the arrangement of the CA-NTD domains was in fact different in all three viruses when observed at higher-resolution.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Comparison of capsid quaternary arrangements found in all three viruses revealed that it is conserved for the CA-CTD domains.
“Comparison of capsid quaternary arrangements found in all three viruses revealed that it is conserved for the CA-CTD domains”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Intra-hexameric interactions were formed by the top of helix 4 and the region spanning helix 5 and 6 in the adjacent monomer.
“Intra-hexameric interactions were formed by the top of helix 4 and the region spanning helix 5 and 6 in the adjacent monomer.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Inter-hexameric CA-NTD contacts involved homo-dimeric and homo-trimeric interfaces in helices 1 and 2, respectively.
“Inter-hexameric CA-NTD contacts involved homo-dimeric and homo-trimeric interfaces in helices 1 and 2, respectively.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
The arrangement of the CA-NTD is not conserved between retroviruses, while that of the CA-CTD is largely conserved.
“Firstly, as described above, the arrangement of the CA-NTD is not conserved between retroviruses, while that of the CA-CTD is largely conserved”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
The MHR was in a position where it could contribute contacts stabilizing the hexamer ring around the central 6-fold.
“The MHR was in a position where it could contribute contacts stabilizing the hexamer ring around the central 6-fold.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Recent improvements in cryo-ET acquisition and data processing protocols allowed the structure of CA within native immature HIV-1 virus particles to be determined to subnanometer resolution.
“Recent improvements in cryo-ET acquisition and data processing protocols [28] allowed the structure of CA within native immature HIV-1 virus particles to be determined to subnanometer resolution”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Downstream of CA, rod-like densities were consistent with the presence of a 6-helix bundle formed by residues of CA and SP1.
“Downstream of CA, rod-like densities were consistent with the presence of a 6-helix bundle formed by residues of CA and SP1.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Dimeric inter-hexamer interactions at the CA-CTD level were in agreement with earlier studies and involved hydrophobic residues in helix 9.
“Dimeric inter-hexamer interactions at the CA-CTD level were in agreement with earlier studies and involved hydrophobic residues in helix 9”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Current low-resolution structures of the immature lattice suggest that the hairpin could be accommodated in the immature lattice, and high-resolution structures of the mature hexamer do not reveal a clear stabilizing role for the hairpin.
“Current low-resolution structures of the immature lattice suggest, however, that the hairpin could be accommodated in the immature lattice [29 ], and high-resolution structures of the mature hexamer do not reveal a clear stabilizing role for the hairpin.”
From Retrovirus maturation-an extraordinary structural transformation (2016) · cites this paper as [29]
Cites
Specific incorporation of cyclophilin A into HIV-1 virions
Franke, E. K., Yuan, H. E. H., & Luban, J. (1994) · Nature · doi:10.1038/372359a0 · Cited by 745 · see citing works
Structure and assembly of immature HIV
Briggs, J. A. G., Riches, J. D., Glass, B., Bartonova, V., Zanetti, G., & Kräusslich, H.-G. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903535106 · Cited by 368 · see citing works
Self-citationStructure of the N-terminal 283-residue fragment of the immature HIV-1 Gag polyprotein
Tang, C., Ndassa, Y., & Summers, M. F. (2002) · Nature Structural Biology · doi:10.1038/nsb806 · Cited by 205 · see citing works
Accola, M. A., Höglund, S., & Göttlinger, H. G. (1998) · Journal of Virology · doi:10.1128/jvi.72.3.2072-2078.1998 · Cited by 196 · see citing works
High-resolution structure of a retroviral capsid hexameric amino-terminal domain
Mortuza, G. B., Haire, L. F., Stevens, A., Smerdon, S. J., Stoye, J. P., & Taylor, I. A. (2004) · Nature · doi:10.1038/nature02915 · Cited by 185 · see citing works
Campos-Olivas, R., Newman, J. L., & Summers, M. F. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3475 · Cited by 119 · see citing works
Bharat, T. A. M., Castillo Menendez, L. R., Hagen, W. J. H., Lux, V., Igonet, S., Schorb, M., Schur, F. K. M., Kräusslich, H.-G., & Briggs, J. A. G. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1401455111 · Cited by 107 · see citing works
Self-citationHydrogen/Deuterium Exchange Analysis of HIV-1 Capsid Assembly and Maturation
Monroe, E. B., Kang, S., Kyere, S. K., Li, R., & Prevelige, P. E. (2010) · Structure · doi:10.1016/j.str.2010.08.016 · Cited by 49 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Retroviral proteases and their roles in virion maturation
Konvalinka, J., Kräusslich, H.-G., & Müller, B. (2015) · Virology · doi:10.1016/j.virol.2015.03.021 · Cited by 148 · see citing works
Self-citationRetrovirus maturation-an extraordinary structural transformation
Mattei, S., Schur, F. K., & Briggs, J. A. (2016) · Current Opinion in Virology · doi:10.1016/j.coviro.2016.02.008 · Cited by 72 · see citing works
Self-citationObr, M., Ricana, C. L., Nikulin, N., Feathers, J.-P. R., Klanschnig, M., Thader, A., Johnson, M. C., Vogt, V. M., Schur, F. K. M., & Dick, R. A. (2021) · Nature Communications · doi:10.1038/s41467-021-23506-0 · Cited by 23 · see citing works
Self-citation
- Authors
- Schur, F. K. M., Hagen, W. J. H., Rumlová, M., Ruml, T., Müller, B., Kräusslich, H.-G., & Briggs, J. A. G.
- Affiliations
- University Hospital Heidelberg (DE)
- European Molecular Biology Laboratory (DE)
- Czech Academy of Sciences (CZ)
- University of Chemistry and Technology, Prague (CZ)
- Corresponding author
- Briggs, John A. G.
- ORCID
- Venue
- Nature
- Published
- 2014-11-02
- Volume
- 517
- Issue
- 7535
- Pages
- 505-508
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2087978946
- Cited by
- 296
- References
- 8
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 16 · 2023: 18 · 2022: 21 · 2021: 21 · 2020: 24 · 2019: 26 · 2018: 30 · 2017: 23 · 2016: 47 · 2015: 50
- FWCI
- 21.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- ASEP (submittedVersion, public-domain)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- HIV-1, immature virus particles, capsid lattice, capsid protein structure, Gag protein, viral assembly, Mason-Pfizer monkey virus, cryo-electron tomography, subtomogram averaging, in situ structural analysis
- MeSH terms
- Capsid, Humans, Models, Molecular, Protein Conformation, Virion, HIV-1, Mason-Pfizer monkey virus, Virus Assembly, Cryoelectron Microscopy, Capsid Proteins, Electron Microscope Tomography, Protein Multimerization, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
