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Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles

Nature Structural & Molecular Biology volume 27, pages 726–734 (2020)Cite this article

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Abstract

The HIV-1 envelope glycoprotein (Env) trimer, composed of gp120 and gp41 subunits, mediates viral entry into cells. Recombinant Env trimers have been studied structurally, but characterization of Env embedded in intact virus membranes has been limited to low resolution. Here, we deploy cryo-electron tomography and subtomogram averaging to determine the structures of Env trimers on aldrithiol-2 (AT-2)-inactivated virions in ligand-free, antibody-bound and CD4-bound forms at subnanometer resolution. Tomographic reconstructions document molecular features consistent with high-resolution structures of engineered soluble and detergent-solubilized Env trimers. One of three conformational states previously predicted by smFRET was not observed by cryo-ET, potentially owing to AT-2 inactivation. We did observe Env trimers to open in situ in response to CD4 binding, with an outward movement of gp120-variable loops and an extension of a critical gp41 helix. Overall features of Env trimer embedded in AT-2-treated virions appear well-represented by current engineered trimers.

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Fig. 1: In situ cryo-ET structure of ligand-free HIV-1 Env trimer.
Fig. 2: Cryo-ET structure of HIV-1 Env in complex with antibodies 10-1074 and 3BNC117 at subnanometer resolution reveals domain features of in situ trimer.
Fig. 3: AT-2 treatment increases the prevalence of state 2 HIV-1 Env on virus.
Fig. 4: In situ cryo-ET structure at 9.7-Å resolution of sCD4D1D2- and 17b-bound Env trimer.
Fig. 5: The central helical density of gp41 in situ resembles that observed in high-resolution SOSIP structures.
Fig. 6: sCD4- and 17b-bound Env trimer adopts a more open conformation in situ in the HR1-N and HR2 regions of gp41.

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Data availability

In situ structures of HIV-1 Env have been deposited to the EMDB with the following codes: EMD-21412 (ligand-free Env), EMD-21411 (CD4- and 17b-bound Env) and EMD-21413 (10-1074- and 3BNC117-bound Env).

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Acknowledgements

This work was supported by the NIH grants RO1AI150560 to W.M., J.L. and S.C.B.; RO1 GM098859 to S.C.B.; PO1 AI150471 to W.M.; by a ViiV research grant to W.M. and J.L.; by an AmfAR (The Foundation for AIDS Research) grant, 109998-67-RKVA, to M.L.; by a grant from National Natural Science Foundation of China (No.31630002) to Z.L.; by the International AIDS Vaccine Initiative’s (IAVI’s) Neutralizing Antibody Consortium to P.D.K.; by the Intramural Research Program of the Vaccine Research Center (NIAID, NIH) to P.D.K.; and by contracts 75N91019D00054 and HHSN261200800001E from the National Cancer Institute, National Institutes of Health, to J.B. and J.D.L. 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.

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  1. These authors contributed equally: Ze Li, Wenwei Li, Maolin Lu.

Authors and Affiliations

  1. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA

    Ze Li, Wenwei Li, Maolin Lu, Walther Mothes & Jun Liu

  2. Microbial Sciences Institute, Yale University, West Haven, CT, USA

    Ze Li, Wenwei Li & Jun Liu

  3. Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Ze Li

  4. AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Julian Bess Jr & Jeffrey D. Lifson

  5. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Cara W. Chao, Jason Gorman, Baoshan Zhang, Tongqing Zhou & Peter D. Kwong

  6. Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Daniel S. Terry & Scott C. Blanchard

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Contributions

W.M., J.L. and P.D.K. conceived the project. W.L. performed cryo-ET experiments and data analysis. Z.L. performed data analysis and modeling, and wrote the manuscript draft. M.L. performed smFRET experiments and analysis. J.B. and J.D.L. provided BAL virions with high Env trimer content. C.W.C. and B.Z. provided sCD4D1D2, 17b, 1010-74 and 3BNC117 (Fabs). J.G. and T.Z. contributed structural analysis. D.S.T. and S.C.B. contributed smFRET technologies and software. J.L., P.D.K. and W.M. supervised all work. Z.L, P.D.K., W.M. and J.L. prepared the manuscript with input from all authors.

Corresponding authors

Correspondence to Walther Mothes or Jun Liu.

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Competing interests

S.C.B. holds an equity interest in Lumidyne Technologies. S.C.B. and W.M. hold the patent US 959385324 B2. W.M. and J.L. are recipients of a ViiV research grant.

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Peer review information Inês Chen was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Comparison of cryo-ET maps of the ligand-free HIV-1/SIV Env trimer.

a, In situ structure of Env trimer on the surface of SIV mac329 virus with truncated cytoplasmic tail (EMD 1246). b, Structure of Env trimer of SIVmneE11S virus (EMD 1216). c, Structure of Env trimer of HIV-1BaL virus (EMD 5019). d, Structure of ligand-free HIV-1BaL Env trimer (current work).

Extended Data Fig. 2 Cryo-ET resolution estimation.

a, Resolution estimation using FSC 0.5 as cutoff value. b, Local resolution estimation of ligand-free, 10-1074 and 3BNC117 double antibodies, and sCD4-17b bound HIV-1BaL Env trimer is estimated with Resmap. For each map, two projections are shown: Z plane projection is shown as a top view, Y plane projection is shown as a side view.

Extended Data Fig. 3 Model fitting. Env trimers from other two strains, omitting the binding antibodies, are rigid body docked into the cryo-ET map.

a, 3H109L and 35O22 bound B41 SOSIP.664 (PDB 6MUF) b, PGT122 and PGV19 bound BG505 NFL.664 (PDB 6B0N). c, Segmented characteristic helical densities of gp41 subunits in the cryo-ET map. d-f, Trimeric HR1C, partial HR1N and HR2 from 4ZMJ fit well into the rod-shape densities.

Extended Data Fig. 4 Visualization of variable loops and glycosylation sites on the top of the ligand-free Env trimer map.

a, Variable loop regions on the top of the Env trimer are differently colored in the map. b, Potential glycosylation densities at the apical surface of BaL strain virus. Ligand-free monomer of fully glycosylated JR-FL∆CT (PDB 5FUU) was docked in the cryo-ET map. The glycan moiety was shown as sticks.

Extended Data Fig. 5 Comparison between the cryo-ET model for HIV-1BaL Env and BG505 SOSIP.664 in complex with different antibody combinations.

Each ligand and its binding protomer were projected into central plane and the dihedral angles were measured with UCSF Chimera. a, Cryo-ET model of 10-1074-3 and BNC117 bound Env. b, 10-1074 bound BG505 SOSIP-based immunogen RC1 (PDB 6ORN). c, 3BNC117 bound BG505 SOSIP.664 (PDB 5V8M). d, 10-1074 and IOMA bound BG505 SOSIP.664 (PDB 5T3Z). All angular values are listed in panel (e).

Extended Data Fig. 6 10-1074 and 3BNC117 cannot stabilize State 1 of AT-2 treated HIV-1BaL Env.

a, b, 10-1074 and 3BNC117 Fabs exhibit a preference for State 1 of virus Env in the absence of AT2-inactivation (a) Representative fluorescence (top, donor Cy3 in green and acceptor Cy5 in red) and FRET trace (bottom, resulting FRET in blue and hidden Markov model idealization in red) of individual V1V4 labeled ligand-free HIV-1NL4-3 virus Env. (b) FRET histogram of HIV-1NL4-3 Env in the presence of broadly neutralization antibodies 10-1074 (50 μg ml−1) and 3BNC117 (50 μg ml−1), overlaid with that of ligand-free HIV-1NL4-3 Env. c, d, 10-1074 and 3BNC117 are unable to restore State 1-predominance observed on native virus Env after AT-2 treatment shifted the conformational equilibrium towards State 2. (c, d) experiments as in (a, b) of AT-2 chemically inactivated HIV-1NL4-3 virus Env, respectively. e, Quantification of relative state occupancy of HIV-1NL4-3 virus Env, derived from FRET histograms in (b, d).

Extended Data Fig. 7 The conformational effect of AT-2 lies in the ectodomain.

FRET histograms of HIV-1JR-FL Env without cytoplasmic tail under conditions: ligand-free and untreated (a); ligand-free Env after AT-2 treatment (b); and in the additional presence of 10-1074 (50 μg ml−1) and 3BNC117 (50 μg ml−1) (c). d, Quantification of the corresponding relative state occupancies.

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Li, Z., Li, W., Lu, M. et al. Subnanometer structures of HIV-1 envelope trimers on aldrithiol-2-inactivated virus particles. Nat Struct Mol Biol 27, 726–734 (2020). https://doi.org/10.1038/s41594-020-0452-2

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