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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Viral Immunology

This article is part of the Research TopicInnovative Immunological Strategies for Overcoming Antimicrobial Resistance and Enhancing Vaccine DevelopmentView all 13 articles

HSV-2 gE2/gI2 are immune evasion molecules that bind IgG Fc to inhibit antibody-dependent cellular cytotoxicity

Provisionally accepted
Giulia TebaldiGiulia Tebaldi1Kevin P. EganKevin P. Egan1Lauren M. HookLauren M. Hook1Tina CairnsTina Cairns2Tomas BergströmTomas Bergström3Kerry S. CampbellKerry S. Campbell4Gary H CohenGary H Cohen2Harvey Michael FriedmanHarvey Michael Friedman1*
  • 1University of Pennsylvania Perelman School of Medicine, Philadelphia, United States
  • 2University of Pennsylvania School of Dental Medicine, Philadelphia, United States
  • 3Goteborgs universitet, Gothenburg, Sweden
  • 4Fox Chase Cancer Center, Philadelphia, United States

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HSV-2 glycoproteins C, D, and E (gC2/gD2.gE2) are immunogens included in an experimental HSV-2 vaccine. We evaluated whether these antigens serve as targets for antibody-dependent cellular cytotoxicity (ADCC). We transiently transfected HEK cells with gC2/gD2/gE2 DNA, added HSV-2 seropositive human convalescent sera (HCS), and measured surface CD107a expression on human NK cells by flow cytometry. We demonstrated that antibodies to gC2/gD2/gE2 mediate ADCC. HSV-2 gE and gI form a complex that binds IgG Fc. We next determined whether gE2/gI2 inhibits ADCC, a crucial function mediated by the IgG Fc, by comparing ADCC titers when HCS were added to cells transfected with gD2, gI2, and a gE2 mutant (gE2MUT) unable to bind IgG Fc or gD2, gI2, and gE2 wild-type (gE2WT). ADCC titers increased by 6.5-fold when cells were transfected with the gE2MUT versus gE2WT (P<0.001). We then spiked HCS with a gE2 mAb that blocks IgG Fc binding, or with a gE2 mAb that does not block IgG Fc binding. The blocking mAb significantly increased titers, whereas a non-blocking gE2 mAb had no effect (P<0.001). We conclude that gE2/gI2 inhibits ADCC, and that an mAb that targets the gE2 IgG Fc binding domain can prevent this inhibition.

Keywords: Antibody-Dependent Cell Cytotoxicity (ADCC), glycoproteins E and I, HSV-2, Immune Evasion, Virus Fc receptor

Received: 12 Dec 2025; Accepted: 16 Feb 2026.

Copyright: © 2026 Tebaldi, Egan, Hook, Cairns, Bergström, Campbell, Cohen and Friedman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Harvey Michael Friedman

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