Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements

Rory Henderson (), Maolin Lu, Ye Zhou, Zekun Mu, Robert Parks, Qifeng Han, Allen L. Hsu, Elizabeth Carter, Scott C. Blanchard, R J Edwards, Kevin Wiehe, Kevin O. Saunders, Mario J. Borgnia, Alberto Bartesaghi, Walther Mothes, Barton F. Haynes, Priyamvada Acharya () and S. Munir Alam ()
Additional contact information
Rory Henderson: Duke University School of Medicine
Maolin Lu: Yale University School of Medicine
Ye Zhou: Duke University
Zekun Mu: Duke University School of Medicine
Robert Parks: Duke University School of Medicine
Qifeng Han: Duke University School of Medicine
Allen L. Hsu: Department of Health and Human Services
Elizabeth Carter: Duke University School of Medicine
Scott C. Blanchard: Weill Cornell Medicine
R J Edwards: Duke University School of Medicine
Kevin Wiehe: Duke University School of Medicine
Kevin O. Saunders: Duke University School of Medicine
Mario J. Borgnia: Department of Health and Human Services
Alberto Bartesaghi: Duke University
Walther Mothes: Yale University School of Medicine
Barton F. Haynes: Duke University School of Medicine
Priyamvada Acharya: Duke University School of Medicine
S. Munir Alam: Duke University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The trimeric HIV-1 Envelope protein (Env) mediates viral-host cell fusion via a network of conformational transitions, with allosteric elements in each protomer orchestrating host receptor-induced exposure of the co-receptor binding site and fusion elements. To understand the molecular details of this allostery, here, we introduce Env mutations aimed to prevent CD4-induced rearrangements in the HIV-1 BG505 Env trimer. Binding analysis and single−molecule Förster Resonance Energy Transfer confirm that these mutations prevent CD4-induced transitions of the HIV-1 Env. Structural analysis by single−particle cryo-electron microscopy performed on the BG505 SOSIP mutant Env proteins shows rearrangements in the gp120 topological layer contacts with gp41. Displacement of a conserved tryptophan (W571) from its typical pocket in these Env mutants renders the Env insensitive to CD4 binding. These results reveal the critical function of W571 as a conformational switch in Env allostery and receptor-mediated viral entry and provide insights on Env conformation that are relevant for vaccine design.

Date: 2020
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DOI: 10.1038/s41467-019-14196-w

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