Year: 2025
Type: article
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.
Source: Nature Communications
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, U.S. Department of Health and Human Services, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Division of Electrical, Communications and Cyber Systems
Awards: NNCI: North Carolina Research Triangle Nanotechnology Network (RTNN), G1676019983, G3194372699, G3275407028, Probing real-time conformational dynamics and allosteric cooperativity of the HIV-1 envelope glycoprotein during virus entry, G4515301176, G4612782523, G5097976226, G5973914729, G6140928607, Data commons for 'omic, microscopy and analysis core facilities, G6810723037, The role of conformational dynamics of enveloped virus spike proteins in cell entry, Duke Center for HIV Structural Biology, Structural definition of CD4-induced HIV-1 Env conformational changes required for infection
OpenAlex ID: W4410455638