Associating HIV-1 envelope glycoprotein structures with states on the virus observed by smFRET

Maolin Lu, Xiaochu Ma, Luis R. Castillo-Menendez, Jason Gorman, Nirmin Alsahafi, Utz Ermel, Daniel S. Terry, Michael Chambers, Dongjun Peng, Baoshan Zhang, Tongqing Zhou, Nick Reichard, Kevin Wang, Jonathan R. Grover, Brennan P. Carman, Matthew R. Gardner, Ivana Nikić-Spiegel, Akihiro Sugawara, James Arthos, Edward A. Lemke, Amos B. Smith, Michael Farzan, Cameron Abrams, James B. Munro, Adrian B. McDermott, Andrés Finzi, Peter D. Kwong, Scott C. Blanchard (), Joseph G. Sodroski () and Walther Mothes ()
Additional contact information
Maolin Lu: Yale University School of Medicine
Xiaochu Ma: Yale University School of Medicine
Luis R. Castillo-Menendez: Dana-Farber Cancer Institute
Jason Gorman: National Institutes of Health
Nirmin Alsahafi: McGill University
Utz Ermel: Yale University School of Medicine
Daniel S. Terry: Weill Cornell Medicine
Michael Chambers: National Institutes of Health
Dongjun Peng: National Institutes of Health
Baoshan Zhang: National Institutes of Health
Tongqing Zhou: National Institutes of Health
Nick Reichard: Yale University School of Medicine
Kevin Wang: Yale University School of Medicine
Jonathan R. Grover: Yale University School of Medicine
Brennan P. Carman: Yale University School of Medicine
Matthew R. Gardner: The Scripps Research Institute
Ivana Nikić-Spiegel: University of Tuebingen
Akihiro Sugawara: University of Pennsylvania
James Arthos: National Institutes of Health
Edward A. Lemke: Johannes Gutenberg University Mainz
Amos B. Smith: University of Pennsylvania
Michael Farzan: The Scripps Research Institute
Cameron Abrams: Drexel University
James B. Munro: Tufts University School of Medicine
Adrian B. McDermott: National Institutes of Health
Andrés Finzi: McGill University
Peter D. Kwong: National Institutes of Health
Scott C. Blanchard: Weill Cornell Medicine
Joseph G. Sodroski: Dana-Farber Cancer Institute
Walther Mothes: Yale University School of Medicine

Nature, 2019, vol. 568, issue 7752, 415-419

Abstract: Abstract The HIV-1 envelope glycoprotein (Env) trimer mediates cell entry and is conformationally dynamic1–8. 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-1JR-FL strain in complex with the antibody PGT15119. 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 pre-triggered 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.

Date: 2019
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DOI: 10.1038/s41586-019-1101-y

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