Conformational trajectory of the HIV-1 fusion peptide during CD4-induced envelope opening
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...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59721-2 |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |