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Herpes simplex virus (HSV) fusion and entry is mediated by a cascade of interactions among gB, gD and gH/gL. The gB homotrimer undergoes a conformational transition from a metastable prefusion state to a more stable postfusion form, driving fusion of the viral envelope and a host cell membrane. An H516P mutation in gB domain III restricts formation of the extended core alpha helix and constrains gB in a prefusion state. Several prefusion gB structures have been determined that contain this mutation. We assessed the antigenic reactivity of gB H516P by quantitative immunodotblot using a panel of gB-reactive monoclonal antibodies All antibodies tested bound to both prefusion (H516P) gB and wild type gB. Antibodies tested to gB domains II, IV and V exhibited differential binding to H516P gB compared to wild type gB. The results suggest that gB H516P has a distinct antigenic profile. The antigenic signature of H516P may be useful as a rapid indicator of prefusion forms of gB. The low pH environment of the cellular endosome is a cell-specific factor for HSV entry and triggers antigenic changes in gB. The step at which low pH impacts gB refolding to execute fusion is not well-understood. The results suggest that gB H516P undergoes wild-type-like conformational changes in gB domains I and V triggered by low pH. We propose that pH acts on an early stage of gB fusion function, prior to extension of the domain III core helix.
Makio et al. (2026) studied this question.