Structural basis for potent antibody-mediated neutralization of human cytomegalovirus

See allHide authors and affiliations

Science Immunology  30 Jun 2017:
Vol. 2, Issue 12, eaan1457
DOI: 10.1126/sciimmunol.aan1457

Function follows form

Congenital human cytomegalovirus (HCMV) is the most common infectious cause of disabilities in newborn infants and the leading cause of deafness in children, highlighting the need for a vaccine that induces neutralizing antibodies to block maternal-fetal transmission of HCMV. Now, Chandramouli et al. report crystal structures of neutralizing antibodies bound to the HCMV pentameric complex (Pentamer), a key determinant of viral entry. These structural and functional studies identify potential entry receptor–binding sites on Pentamer as well as other functional sites that may serve as targets for vaccine development and antibody and small-molecule therapeutics.


Human cytomegalovirus (HCMV) is the leading viral cause of birth defects and organ transplant rejection. The HCMV gH/gL/UL128/UL130/UL131A complex (Pentamer) is the main target of humoral responses and thus a key vaccine candidate. We report two structures of Pentamer bound to human neutralizing antibodies, 8I21 and 9I6, at 3.0 and 5.9 Å resolution, respectively. The HCMV gH/gL architecture is similar to that of Epstein-Barr virus (EBV) except for amino-terminal extensions on both subunits. The extension of gL forms a subdomain composed of a three-helix bundle and a β hairpin that acts as a docking site for UL128/UL130/UL131A. Structural analysis reveals that Pentamer is a flexible molecule, and suggests sites for engineering stabilizing mutations. We also identify immunogenic surfaces important for cellular interactions by epitope mapping and functional assays. These results can guide the development of effective vaccines and immunotherapeutics against HCMV.

View Full Text

Stay Connected to Science Immunology