Orthoherpesviridae are a large family of enveloped viruses that cause lifelong infections in many species including humans. These viruses penetrate target host cells by fusing their lipid envelopes with cellular membrane. The viral entry process is orchestrated by several viral envelope glycoproteins. In herpes simplex viruses (HSV)—the prototypical Orthoherpesviridae that cause skin sores in humans—viral entry requires glycoproteins gD, gB, and gH/gL. Whereas gD binds the host receptor, gB mediates membrane fusion of the host cell and the viral envelope, and gH/gL transmits the activating signal from gD to gB. However, how gH/gL achieves this is unclear. Signal transmission likely requires conformational changes in gH/gL, but currently, only one conformation of gH/gL has been characterized. Here, we report cryogenic electron microscopy (cryoEM) structures of the HSV-2 gH ecto /gL bound to fragments of antigen binding (Fabs) of several anti-gH/gL monoclonal antibodies that block membrane fusion. Comparison with the known gH/gL structure reveals several major conformational differences. We hypothesize that these conformational differences reflect conformational changes in gH/gL during signal transmission from gD to gB.
Russell et al. (2026) studied this question.
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