Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion

Creators: Wang, Haoqing; Barnes, Christopher O.; Yang, Zhi; Nussenzweig, Michel C.; Bjorkman, Pamela J.

Abstract

HIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and opening Env to enable gp41-mediated fusion. We present 3.54 Å and 4.06 Å cryoelectron microscopy structures of partially open soluble native-like Env trimers (SOSIPs) bound to CD4. One structure, a complex with a coreceptor-mimicking antibody that binds both CD4 and gp120, stabilizes the displaced V1V2 and reveals its structure. Comparing partially and fully open Envs with closed Envs shows that gp41 rearrangements are independent of the CD4-induced rearrangements that result in V1V2 displacement and formation of a 4-stranded bridging sheet. These findings suggest ordered conformational changes before coreceptor binding: (1) gp120 opening inducing side-chain rearrangements and a compact gp41 central helix conformation, and (2) 4-stranded bridging-sheet formation and V1V2 displacement. These analyses illuminate potential receptor-induced Env changes and inform design of therapeutics disrupting viral entry.

Additional Information

© 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Received 3 July 2018, Revised 20 July 2018, Accepted 5 September 2018, Available online 10 October 2018. We thank Zhiheng Yu, Chuan Hong, Rick Huang, and Dan Shi (Janelia Farm) for assistance with cryo-EM data collection and motion correction; Andrey Malyutin and Songye Chen for assistance with grid preparation; Jost Vielmetter and the Caltech Protein Expression Center for transfections and protein expression; Al Cupo and John Moore (Weill Cornell Medical College) for the stable cell line expressing B41 SOSIP; James Robinson (Tulane University) for the 21c hybridoma; and members of the Bjorkman and Grant Jensen laboratories for helpful discussions and critical reading of the manuscript. This research was supported by NIH grant 2 P50 GM082545-06 (to P.J.B.), National Institute of Allergy and Infectious Diseases of the NIH grant HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), and the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery grant 1040753 (to P.J.B. and M.C.N.). M.C.N. is an HHMI investigator. Research support was also provided by the Hanna Gray Fellowship Program from the Howard Hughes Medical Institute and the Postdoctoral Enrichment Program from the Burroughs Wellcome Fund (C.O.B.). We thank the Gordon and Betty Moore and Beckman Foundations for gifts to Caltech to support electron microscopy. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Author Contributions: H.W., C.O.B., M.C.N., and P.J.B. designed the research; H.W. and C.O.B. performed research; H.W., C.O.B., Z.Y., and P.J.B. analyzed data; and H.W., C.O.B., and P.J.B. wrote the paper. The authors declare no competing interests.

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