Journal
NATURE
Volume 568, Issue 7752, Pages 415-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41586-019-1101-y
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Funding
- NIH [RO1 GM116654, UM1 AI100645, RO1 GM098859, RO1 AI124982, RO1 AI100645, K22 AI116262]
- CRC [RCHS0235]
- CIHR foundation [352417, PO1 GM056550]
- Brown Coxe Fellowship
- China Scholarship Council
- International AIDS Vaccine Initiative's (IAVI's) Neutralizing Antibody Consortium
- Intramural Research Program of the Vaccine Research Center (NIAID, NIH)
- Emmy-Noether programme of the German Research Foundation [317530061]
- [SFB1129]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZICAI005114, ZIAAI005023, ZIAAI005143, ZIAAI000883] Funding Source: NIH RePORTER
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The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic(1-8.) Imaging by single-molecule fluorescence resonance energy transfer (smFRET) has revealed that, on the surface of intact virions, mature pre-fusion Env transitions from a pre-triggered conformation (state 1) through a default intermediate conformation (state 2) to a conformation in which it is bound to three CD4 receptor molecules (state 3)(8-10). It is currently unclear how these states relate to known structures. Breakthroughs in the structural characterization of the HIV-1 Env trimer have previously been achieved by generating soluble and proteolytically cleaved trimers of gp140 Env that are stabilized by a disulfide bond, an isoleucine-to-proline substitution at residue 559 and a truncation at residue 664 (SOSIP. 664 trimers)(5,11-18). Cryo-electron microscopy studies have been performed with C-terminally truncated Env of the HIV-1(JR-FL) strain in complex with the antibody PGT151(19). Both approaches have revealed similar structures for Env. Although these structures have been presumed to represent the pre-triggered state 1 of HIV-1 Env, this hypothesis has never directly been tested. Here we use smFRET to compare the conformational states of Env trimers used for structural studies with native Env on intact virus. We find that the constructs upon which extant high-resolution structures are based predominantly occupy downstream conformations that represent states 2 and 3. Therefore, the structure of the pretriggered state-1 conformation of viral Env that has been identified by smFRET and that is preferentially stabilized by many broadly neutralizing antibodies-and thus of interest for the design of immunogens-remains unknown.
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