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PLoS Pathog. 2015 Oct 20;11(10):e1005230. doi: 10.1371/journal.ppat.1005230. eCollection 2015 Oct.

Antigenic Characterization of the HCMV gH/gL/gO and Pentamer Cell Entry Complexes Reveals Binding Sites for Potently Neutralizing Human Antibodies.

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Novartis Vaccines (a GSK company), Cambridge, Massachusetts, United States of America.
ETH Zürich, Department of Biology, Institute of Molecular Systems Biology, Zürich, Switzerland.
Novartis Vaccines (a GSK company), Siena, Italy.
Harvard University, Department of Molecular and Cellular Biology, Cambridge, Massachusetts, United States of America; Harvard Medical School, Department of Cell Biology, Boston, Massachusetts, United States of America.
ETH Zürich, Department of Biology, Institute of Molecular Systems Biology, Zürich, Switzerland; Faculty of Science, University of Zurich, Zurich, Switzerland.


Human Cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and in fetuses following congenital infection. The glycoprotein complexes gH/gL/gO and gH/gL/UL128/UL130/UL131A (Pentamer) are required for HCMV entry in fibroblasts and endothelial/epithelial cells, respectively, and are targeted by potently neutralizing antibodies in the infected host. Using purified soluble forms of gH/gL/gO and Pentamer as well as a panel of naturally elicited human monoclonal antibodies, we determined the location of key neutralizing epitopes on the gH/gL/gO and Pentamer surfaces. Mass Spectrometry (MS) coupled to Chemical Crosslinking or to Hydrogen Deuterium Exchange was used to define residues that are either in proximity or part of neutralizing epitopes on the glycoprotein complexes. We also determined the molecular architecture of the gH/gL/gO- and Pentamer-antibody complexes by Electron Microscopy (EM) and 3D reconstructions. The EM analysis revealed that the Pentamer specific neutralizing antibodies bind to two opposite surfaces of the complex, suggesting that they may neutralize infection by different mechanisms. Together, our data identify the location of neutralizing antibodies binding sites on the gH/gL/gO and Pentamer complexes and provide a framework for the development of antibodies and vaccines against HCMV.

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