Prefusion structure, evasion and neutralization of HSV-1 glycoprotein B
Glycoprotein B (gB) refolds between prefusion and postfusion conformations to facilitate herpesvirus entry into host cells. However, the isolation of prefusion-specific neutralizing antibodies, effective against other viral entry machines, has been challenging. Here we describe stabilization of the prefusion gB ectodomain from herpes simplex virus 1 (HSV-1), determine ectodomain structures at 2.9- to 4.1-Å resolution using cryogenic electron microscopy (cryo-EM) and isolate a prefusion-specific gB-neutralizing antibody termed WS.HSV-1.24. Murine immunization with gB stabilized in the prefusion conformation induced high titres of antibodies binding to both prefusion and postfusion gB, but-most notably-without measurable serum neutralization. Accessibility analysis revealed iso-surface exposure, with accessible surfaces on prefusion HSV-1 gB also exposed on postfusion gB. Structural analysis suggested substantial plasticity, with regions that refolded between pre- and postfusion conformations relegated to domain interfaces with limited accessibility; indeed, WS.HSV-1.24 recognized a domain-interface refolding region to facilitate neutralization. We propose that prefusion HSV-1 gB evades neutralization by most antibodies through an iso-surface display that is coupled to structural plasticity.
Authors
- Tongqing Zhou (ORCID: https://orcid.org/0000-0002-3935-4637)
- Fabiana Bahna
- Adam S. Olia (ORCID: https://orcid.org/0000-0003-0805-1331)
- Andrea Biju (ORCID: https://orcid.org/0000-0001-7405-3373)
- Malcolm L. Wells
- Yicheng Guo (ORCID: https://orcid.org/0000-0001-5357-660X)
- Peter D. Kwong (ORCID: https://orcid.org/0000-0003-3560-232X)
- Theodore C. Pierson (ORCID: https://orcid.org/0000-0002-3795-4348)
- David D. Ho (ORCID: https://orcid.org/0000-0003-1627-149X)
- Anum Glasgow (ORCID: https://orcid.org/0000-0002-0938-881X)
- Maple Wang
- Yaoxing Huang (ORCID: https://orcid.org/0000-0001-6270-1644)
- Phinikoula S. Katsamba (ORCID: https://orcid.org/0000-0003-3981-1604)
- Lawrence Shapiro (ORCID: https://orcid.org/0000-0001-9943-8819)
- Yosef Sabo (ORCID: https://orcid.org/0000-0002-4973-8247)
- Ryan S. Roark (ORCID: https://orcid.org/0000-0003-0586-103X)
- Seetha Mannepalli
- Wei Shi (ORCID: https://orcid.org/0000-0002-4770-6444)
- S. Chong (ORCID: https://orcid.org/0000-0003-1829-5540)
- Andrew J. Schaub (ORCID: https://orcid.org/0000-0001-7770-7045)
- Mehin Suleiman (ORCID: https://orcid.org/0009-0009-5862-4266)
- Cheng Cheng (ORCID: https://orcid.org/0000-0002-3837-9293)
- Reda Rawi (ORCID: https://orcid.org/0000-0002-0445-2325)
- Li Ou (ORCID: https://orcid.org/0000-0001-5653-8684)
- Baoshan Zhang (ORCID: https://orcid.org/0000-0002-0165-1513)
- Jordan E. Becker
- Haijuan Du
- Hsiang Hong (ORCID: https://orcid.org/0009-0007-8657-5479)
- Sarah K. Rubin
Institutions
- National Institutes of Health (US)
- Aaron Diamond AIDS Research Center (US)
- Columbia University Irving Medical Center (US)
- National Institute of Allergy and Infectious Diseases (US)
- Columbia University (US)
Publication Details
- Journal
- Nature Microbiology
- Published
- 2025-10-31
- DOI
- https://doi.org/10.1038/s41564-025-02153-x
- Citations
- 8
- Primary Topic
- Herpesvirus Infections and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 10.83