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Post-fusion ectodomain of HSV-1 gB in complex with BMPC-23 Fab
Structural highlights
FunctionGB_HHV1K Envelope glycoprotein that forms spikes at the surface of virion envelope. Essential for the initial attachment to heparan sulfate moities of the host cell surface proteoglycans. Involved in fusion of viral and cellular membranes leading to virus entry into the host cell. Following initial binding of gD to one of its receptors, membrane fusion is mediated by the fusion machinery composed at least of gB and the heterodimer gH/gL. May also be involved in the fusion between the virion envelope and the outer nuclear membrane during virion egress. Also plays a role, together with gK, in virus-induced cell-to-cell fusion (syncytia formation).[1] Publication Abstract from PubMedThere is an unmet need for monoclonal antibodies (mAbs) for prevention or as adjunctive treatment of herpes simplex virus (HSV) disease. Most vaccine and mAb efforts focus on neutralizing antibodies, but for HSV this strategy has proven ineffective. Preclinical studies with a candidate HSV vaccine strain, DeltagD-2, demonstrated that non-neutralizing antibodies that activate Fcgamma receptors (FcgammaRs) to mediate antibody-dependent cellular cytotoxicity (ADCC) provide active and passive protection against HSV-1 and HSV-2. We hypothesized that this vaccine provides a tool to identify and characterize protective mAbs. We isolated HSV-specific mAbs from germinal center and memory B cells and bone marrow plasmacytes of DeltagD-2-vaccinated mice and evaluated these mAbs for binding, neutralizing, and FcgammaR-activating activity and for protective efficacy in mice. The most potent protective mAb, BMPC-23, was not neutralizing but activated murine FcgammaRIV, a biomarker of ADCC. The cryo-electron microscopic structure of the Fab-glycoprotein B (gB) assembly identified domain IV of gB as the epitope. A single dose of BMPC-23 administered 24 hours before or after viral challenge provided significant protection when configured as mouse IgG2c and protected mice expressing human FcgammaRIII when engineered as a human IgG1. These results highlight the importance of FcR-activating antibodies in protecting against HSV. A non-neutralizing glycoprotein B monoclonal antibody protects against herpes simplex virus disease in mice.,Kuraoka M, Aschner CB, Windsor IW, Mahant AM, Garforth SJ, Kong SL, Achkar JM, Almo SC, Kelsoe G, Herold BC J Clin Invest. 2023 Feb 1;133(3):e161968. doi: 10.1172/JCI161968. PMID:36454639[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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