The native conformational landscape and priming mechanism of herpes simplex virus glycoprotein B
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A structural study reports cryo-EM structures of HSV-1 glycoprotein B (gB) taken from virions, finding mainly a prefusion state and a minor intermediate primed state. The authors also captured a further intermediate, the deep-primed state, in a mutant and engineered gB mutants locked in distinct conformations. The work is structural and laboratory-based; no immunization or protection data are reported, and the authors frame the mutants as intended for future vaccine evaluation.
The authors describe stabilizing gB in its prefusion conformation as a primary strategy for vaccine development. In the virion-derived sample, the predominant population (73% of particles) exhibited a compact central helix bundle with a closed tip, while the minor population (27%) displayed a cracked appearance. The authors state they cannot rule out that this difference simply reflects the intrinsic dynamics of gB.
A tethering helix, described as unique to alpha-herpesviruses, cross-links adjacent protomers and stabilizes these conformations. A mutant designed to disrupt this helix lost the ability to induce cell-cell fusion in a virus-free assay and showed only the postfusion structure. The authors engineered mutants locked in distinct conformational states, with one mutant showing only primed particles.
The authors describe these mutants as intended for future vaccine evaluation, and whether they would work as vaccine immunogens is not reported.
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- The authors determined cryo-EM structures of HSV-1 glycoprotein B (gB) taken from virions, finding mainly a prefusion state and a minor intermediate primed state.
- In the virion-derived sample, the predominant population had a compact, closed central helix bundle and a minor population had a cracked appearance.
- A tethering helix, described as unique to alpha-herpesviruses, cross-links adjacent protomers and stabilizes these conformations.
- A gB mutant designed to disrupt the tethering helix lost the ability to induce cell-cell fusion in a virus-free assay and showed only the postfusion structure.
- A further downstream intermediate, named the deep-primed state, was captured in a mutant.
- The authors engineered gB mutants locked in distinct conformational states; one mutant showed only primed particles.
- The authors state they cannot rule out that the closed-versus-open difference simply reflects intrinsic gB dynamics rather than a distinct primed state.
- The authors frame the structures as a basis for designing gB-based vaccines; the mutants are described as intended for future vaccine evaluation.
- The authors describe stabilizing gB in its prefusion conformation as a primary strategy for vaccine development.