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

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.

Citation: 

Henderson, Rory, Maolin Lu, Ye Zhou, Zekun Mu, Robert Parks, Qifeng Han, Allen L. Hsu, et al. “Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements.” Nat Commun 11, no. 1 (January 24, 2020): 520. https://doi.org/10.1038/s41467-019-14196-w.

Published Date: 
Friday, January 24, 2020
Published In: 
Nature Communications
PMID: 
31980614