Structural characterization of antibodies for synergistic HCMV neutralization

The limited mechanistic understanding of Human Cytomegalovirus (HCMV) infection and neutralization has hindered the effective application of antibodies for HCMV prevention and therapy. To address this, we conducted high-resolution cryo-EM analysis of 17 human monoclonal antibodies targeting HCMV glycoproteins gH and gL. This analysis revealed a landscape of vulnerable epitopes, including detailed binding modes, spatial orientations, and structural features associated with distinct neutralization phenotypes. By comprehensively characterizing the neutralizing properties of these antibodies and their combinations, we identified synergistic antibody cocktails that enhance the neutralization capacity of individual antibodies. Notably, while single antibodies only partially neutralized HCMV, their synergistic combinations achieved substantially more complete inhibition. Together, these findings delineate structural correlates of HCMV neutralization and establish functional principles for antibody-based combinatorial targeting of HCMV.