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Distribution and three-dimensional structure of AIDS virus envelope spikes

Nature volume 441, pages 847–852 (2006)Cite this article

Abstract

Envelope glycoprotein (Env) spikes on AIDS retroviruses initiate infection of host cells and are therefore targets for vaccine development. Though crystal structures for partial Env subunits are known, the structure and distribution of native Env spikes on virions is obscure. We applied cryoelectron microscopy tomography to define ultrastructural details of spikes. Virions of wild-type human immunodeficiency virus 1 (HIV-1) and a mutant simian immunodeficiency virus (SIV) had ∼14 and ∼73 spikes per particle, respectively, with some clustering of HIV-1 spikes. Three-dimensional averaging showed that the surface glycoprotein (gp120) ‘head’ of each subunit of the trimeric SIV spike contains a primary mass, with two secondary lobes. The transmembrane glycoprotein ‘stalk’ of each trimer is composed of three independent legs that project obliquely from the trimer head, tripod-like. Reconciling available atomic structures with the three-dimensional whole spike density map yields insights into the orientation of Env spike structural elements and possible structural bases of their functions.

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Figure 1: Representative tomographic images of mutant SIV and wild-type HIV-1.
Figure 2: Surface-rendered models of a representative SIV (a) and three HIV-1 (b–d) virions with highlighted (white) presumptive Env spikes.
Figure 3: Surface-rendered model of averaged SIV Env spike tomograms.
Figure 4: Surface-rendered model of SIV Env spike manually fitted with SIV unliganded core atomic model.
Figure 5: Fitting of 2F5 and 4E10 peptides.

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Acknowledgements

We thank H. Winkler for assistance with volume alignment and classification and 3D volume pickup and P. D. Kwong for his comments on the manuscript. The work was supported in part by a NIH and NCI contract (J.B., E.C., J.D.L.) and grants from the NIH NIAID (P.Z., H.G., K.H.R.) and the NIH NIGMS (J.L., K.A.T.). This project has been funded in whole or in part with federal funds from the National Cancer Institute, NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.Author Contributions P.Z. performed the bulk of the cryoEM, image analysis, model fitting, and graphic illustration. J.L. assisted with the image acquisition, analysis and interpretation. J.B. cultured and purified the viruses. E.C. biochemically analysed the virus preparations for purity. J.D.L. contributed to the design of the project and contributed extensively to the manuscript writing. H.G. assisted with fitting of the 2F5 and 4E10 peptides and MAbs into the cryoEM density map. G.A.O. contributed to the analysis of the data, particularly as it relates to the transmembrane region of the envelope spike. K.A.T. provided technical expertise on various aspects of the cryoEM and tomography and contributed to technical portions of the manuscript. K.H.R. provided overall management of the project as well as data interpretation, manuscript writing and figure design.

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Authors and Affiliations

  1. Department of Biological Science and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, 32306, USA

    Ping Zhu, Jun Liu, Henry Grisé, Kenneth A. Taylor & Kenneth H. Roux

  2. AIDS Vaccine Program, SAIC Frederick Inc, National Cancer Institute at Frederick, Frederick, Maryland, 21702, USA

    Julian Bess Jr, Elena Chertova & Jeffrey D. Lifson

  3. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Gilad A. Ofek

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Correspondence to Kenneth H. Roux.

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Supplementary information

Supplementary Notes

This file contains Supplementary Methods, Supplementary Figure Legends, and Supplementary Movie Legends and additional references. (DOC 46 kb)

Supplementary Figure 1

Distribution of inter-spike centre-to-centre distances for mutant SIV and wtHIV-1. (JPG 78 kb)

Supplementary Figure 2

Distribution of Env spike cluster sizes on 40 HIV-1 virions compared with the distribution of clusters on hypothetical model virions with randomly placed Env spikes calculated, as described for Supplementary Figure 1. (JPG 45 kb)

Supplementary Figure 3

Inherent three-fold symmetry in Env spike averaged images. (JPG 76 kb)

Supplementary Figure 4

Z-stack of 42 sequential density sections through the 3-fold axis of the final Env spike average. (JPG 77 kb)

Supplementary Figure 5

Comparison of gp120 fitted trimer models. (JPG 148 kb)

Supplementary Figure 6

Density distribution profile of the cryoEM trimer slice through the final Env spike average showing the minimum separation between distinguishable internal density peaks measuring 3.2 nm. (JPG 44 kb)

Supplementary Movie 1

CryoEM tomogram of SIV virions and corresponding isosurface model. (MOV 9749 kb)

Supplementary Movie 2

CryoEM spike Env model. (MOV 9115 kb)

Supplementary Movie 3

De novo fitting of gp120 atomic model into cryoEM isosurface model. (MOV 9282 kb)

Supplementary Movie 4

CryoEM isosurface model manually fitted with gp41 peptides and docked with MAbs. (MOV 8508 kb)

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Zhu, P., Liu, J., Bess, J. et al. Distribution and three-dimensional structure of AIDS virus envelope spikes. Nature 441, 847–852 (2006). https://doi.org/10.1038/nature04817

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