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<p>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.</p>

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Prefusion structure, evasion and neutralization of HSV-1 glycoprotein B

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月31日

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  • Ryan S. Roark,
  • Andrew J. Schaub,
  • Wei Shi,
  • Maple Wang,
  • Fabiana A. Bahna,
  • Jordan E. Becker,
  • Andrea Biju,
  • Sue Chong,
  • Haijuan Du,
  • Yicheng Guo,
  • Hsiang Hong,
  • Phinikoula S. Katsamba,
  • Seetha M. Mannepalli,
  • Adam S. Olia,
  • Li Ou,
  • Sarah K. Rubin,
  • Yosef Sabo,
  • Mehin Suleiman,
  • Malcolm L. Wells,
  • Baoshan Zhang,
  • Cheng Cheng,
  • Anum Glasgow,
  • David D. Ho,
  • Yaoxing Huang,
  • Theodore C. Pierson,
  • Reda Rawi,
  • Tongqing Zhou,
  • Lawrence Shapiro,
  • Peter D. Kwong

摘要

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.