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Abstract

Elephant endotheliotropic herpesvirus (EEHV) causes a fatal haemorrhagic disease in young elephants and represents a major threat to the survival of these endangered species. Despite its clinical importance, the mechanisms of EEHV entry and host cell recognition remain poorly understood. Here, we show that the EEHV1A homolog of the Betaherpesvirus glycoprotein O (gO) assembles with glycoproteins H and L (gH/gL) to form a heterotrimeric complex analogous to the human cytomegalovirus (HCMV) gH/gL/gO trimer. Using single-particle cryo-electron microscopy, we determined the structure of the EEHV1A gH/gL/gO complex at 3.2 [A] resolution, revealing a conserved overall architecture but distinct gO topology and disulfide arrangement. The EEHV1A trimer, but not gH/gL alone, bound primary elephant endothelial cells, monocytes, and lymphocytes, indicating that gH/gL/gO serves as the receptor-binding complex of EEHV1A. This binding was specifically blocked by sera from naturally infected elephants, confirming its antigenic relevance. Finally, negative-stain electron microscopy polyclonal epitope mapping of gH/gL/gO-Fab complexes identified a Fab population that bound gO near the apex of the gH/gL/gO trimer, suggesting that these antibodies may interfere with gH/gL/gO-receptor interactions. Together, these findings define the molecular architecture and receptor-binding properties of the EEHV1A gH/gL/gO complex and provide a structural framework for the development of vaccines and antibody-based interventions against EEHV-associated disease.

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