Structural and biochemical studies of HCMV gH/gL/gO and Pentamer reveal mutually exclusive cell entry complexes

Abstract

Significance Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and in fetuses after congenital infection. gH/gL/gO and Pentamer are targets for neutralizing antibodies. We show that gO and UL128/UL130/UL131A bind to the same site on gH/gL through formation of a disulfide bond with gL-Cys144. The alternative use of this binding site by either gO or the ULs may provide a mechanism for cell tropism modulation. Our analysis reveals that gH/gL antigenic sites are conserved among gH/gL, gH/gL/gO, and Pentamer, whereas gH/gL/gO- and Pentamer-specific neutralizing antibody-binding sites are located in the gH/gL N terminus protrusion that contains the gO and the UL subunits. These data support the development of vaccines and antibody therapeutics against HCMV.