Sci Transl Med. 2025 Nov 19;17(825):eadu8579. doi: 10.1126/scitranslmed.adu8579. Epub 2025 Nov 19.
ABSTRACT
Herpes simplex virus (HSV) encodes surface glycoproteins that are host defense evasion molecules. For example, glycoproteins E and I (gE/gI) form a viral Fc receptor (vFcR) for most subclasses and allotypes of human IgG, promoting evasion of humoral immune responses. Although monoclonal antibodies (mAbs) protect mice from neonatal HSV (nHSV) infections, the impact of vFcR activity on mAb-mediated protection is unknown. Using HSV-1 with intact and ablated gE-mediated Fc binding, as well as Fc-engineered mAbs with modified ability to interact with gE/gI, we investigated the role of the vFcR in mAb-mediated protection from nHSV. HSV-specific mAbs modified to lack binding to gE exhibited enhanced neutralization in vitro and superior protection in vivo compared with their native IgG1 forms. Improved protection was dependent on the presence of vFcR activity and was observed for mAbs specific for both glycoprotein D and glycoprotein B, as well as for a nonneutralizing mAb, and for both laboratory-adapted and clinical isolates of HSV-1 and HSV-2. Further, human IgG3 allotypes, including those lacking vFcR binding, also exhibited enhanced antiviral activity in vivo, identifying a unique viral susceptibility to this subclass. In summary, this study demonstrates that rendering mAbs insensitive to the vFcR can improve protection against HSV, offering prospects for antibody-based interventions.
PMID:41259538 | DOI:10.1126/scitranslmed.adu8579
