Conformational trajectory of the HIV-1 fusion peptide during CD4-induced envelope opening

Bhishem Thakur, Revansiddha H. Katte, Wang Xu, Katarzyna Janowska, Salam Sammour, Rory Henderson, Maolin Lu, Peter D. Kwong and Priyamvada Acharya ()
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Bhishem Thakur: Duke University
Revansiddha H. Katte: University of Texas at Tyler Health Science Center
Wang Xu: University of Texas at Tyler Health Science Center
Katarzyna Janowska: Duke University
Salam Sammour: Duke University
Rory Henderson: Duke University
Maolin Lu: University of Texas at Tyler Health Science Center
Peter D. Kwong: Columbia University
Priyamvada Acharya: Duke University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The hydrophobic fusion peptide (FP), a critical component of the HIV-1 entry machinery, is located at the N terminus of the envelope (Env) gp41 subunit. The receptor-binding gp120 subunit of Env forms a heterodimer with gp41. The gp120/gp41 heterodimer assembles into a homotrimer, in which FP is accessible for antibody binding. Env conformational changes or “opening” that follow receptor binding result in FP relocating to a newly formed interprotomer pocket at the gp41-gp120 interface where it is sterically inaccessible to antibodies. The mechanistic steps connecting the entry-related transition of antibody accessible-to-inaccessible FP configurations remain unresolved. Here, using SOSIP-stabilized Env ectodomains, we visualize that the FP remains accessible for antibody binding despite substantial receptor-induced Env opening. We delineate stepwise Env opening from its closed state to a functional CD4-bound symmetrically open Env in which we show that FP was accessible for antibody binding. We define downstream re-organizations that lead to the formation of a gp120/gp41 cavity into which the FP buries to become inaccessible for antibody binding. These findings improve our understanding of HIV-1 entry and delineate the entry-related conformational trajectory of a key site of HIV vulnerability to neutralizing antibody.

Date: 2025
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DOI: 10.1038/s41467-025-59721-2

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