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Assessment of Immunologically Relevant Dynamic Tertiary Structural Features of the HIV-1 V3 Loop Crown R2 Sequence by ab initio Folding
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Dynamic HIV-1 spike motion creates vulnerability for its membrane-bound tripod to antibody attack
Shuang Yang1, Giorgos Hiotis1,2, Yi Wang3,4
1Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY, USA.
Nature Communications
|October 27, 2022
Summary
HIV-1 spike protein's MPER region is accessible via spontaneous tilting, enabling broadly neutralizing antibodies to block viral fusion. This discovery offers new avenues for developing effective HIV vaccines.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- HIV-1 vaccines face challenges due to high viral mutation rates and complex spike protein structure.
- The membrane-proximal external region (MPER) of gp160 is a target for broadly neutralizing antibodies (bnAbs), but MPER-based vaccines have been unsuccessful.
Purpose of the Study:
- To investigate the structural dynamics of the HIV-1 spike protein, specifically the MPER region.
- To understand how bnAbs interact with the MPER and influence viral fusion.
Main Methods:
- Cryo-electron microscopy (cryo-EM) of nanodisc-embedded HIV-1 spike protein.
- Molecular-dynamics simulations to analyze protein behavior and interactions.
Main Results:
- Spike protein ectodomain tilting was observed, revealing previously occluded MPER regions.
- Broadly neutralizing antibodies (bnAbs), such as 4E10, bind to the exposed MPER.
- Antibody binding alters MPER dynamics, modifies ectodomain tilt, and induces strain, abrogating membrane fusion.
Conclusions:
- Spontaneous ectodomain tilting creates a vulnerability in the HIV-1 spike protein.
- Targeting the exposed MPER with bnAbs can inhibit viral fusion.
- These findings provide critical insights for the rational design of next-generation HIV vaccines.
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