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STRUCTURE-FUNCTION ANALYSIS OF PREFUSION FORMS OF HERPES SIMPLEX VIRUS 1 GLYCOPROTEIN B
Dissertation

STRUCTURE-FUNCTION ANALYSIS OF PREFUSION FORMS OF HERPES SIMPLEX VIRUS 1 GLYCOPROTEIN B

Albina Makio Oboya
Doctor of Philosophy (PhD), Washington State University
2026
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Makio-dissertation-REV3-05-29-26AM
Embargoed Access, Embargo ends: 07/20/2028 CC BY-NC-ND V4.0

Abstract

Conformation Glycoprotein B Herpesviruses HSV-1 Postfusion Prefusion Immunology
Herpes simplex virus (HSV) entry involves a highly coordinated membrane fusion mechanism representing a critical determinant of viral tropism, infectivity, and pathogenesis. Despite decades of study and the availability of nucleoside analogue therapies, HSV continues to impose a substantial global health burden due to lifelong latency, recurrent disease, and the emergence of antiviral resistance. Close to two-thirds (67%) of the global population below age 50 have HSV-1and 13% of the same age group are living with HSV-2 infection. A key, yet incompletely resolved, aspect of HSV biology is the molecular basis by which the viral fusion machinery is activated to mediate envelope–cell membrane merger. Current models posit that receptor engagement by glycoprotein D initiates a sequential activation cascade involving the gH/gL heterodimer and glycoprotein B (gB), the conserved class III viral fusogen responsible for executing membrane fusion. However, the precise structural transitions, regulatory checkpoints, and environmental cues that govern this process across diverse cellular contexts remain insufficiently defined. The central hypothesis of this dissertation is that HSV-1 glycoprotein B is regulated by a network of intramolecular interactions that stabilize the prefusion conformation and control the timing of membrane fusion. Specifically, this work, together with previous reports, proposes that contacts between the fusion loops and membrane-proximal region, including the Q181–R747 interaction, modulate the fusion function in gB, whereas the hinge region in Domain III is critical for the formation of the extended α – helix important for gB fusion. Furthermore, this dissertation hypothesizes that mildly acidic pH acts early in the entry process to prime gB for activation before formation of the extended intermediate. By combining mutagenesis, antibody mapping, molecular simulations, and functional assays, this work seeks to define how these structural determinants govern HSV entry and to identify new opportunities for antiviral and vaccine design.

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