Functional screening for anti-CMV biologics identifies a broadly neutralizing epitope of an essential envelope protein

Thomas J. Gardner, Kathryn R. Stein, J. Andrew Duty, Toni M. Schwarz, Vanessa M. Noriega, Thomas Kraus, Thomas M. Moran and Domenico Tortorella ()
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Thomas J. Gardner: Icahn School of Medicine at Mount Sinai
Kathryn R. Stein: Icahn School of Medicine at Mount Sinai
J. Andrew Duty: Icahn School of Medicine at Mount Sinai
Toni M. Schwarz: Icahn School of Medicine at Mount Sinai
Vanessa M. Noriega: Icahn School of Medicine at Mount Sinai
Thomas Kraus: Center for Therapeutic Antibody Development, Icahn School of Medicine at Mount Sinai
Thomas M. Moran: Icahn School of Medicine at Mount Sinai
Domenico Tortorella: Icahn School of Medicine at Mount Sinai

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract The prototypic β-herpesvirus human cytomegalovirus (CMV) establishes life-long persistence within its human host. The CMV envelope consists of various protein complexes that enable wide viral tropism. More specifically, the glycoprotein complex gH/gL/gO (gH-trimer) is required for infection of all cell types, while the gH/gL/UL128/130/131a (gH-pentamer) complex imparts specificity in infecting epithelial, endothelial and myeloid cells. Here we utilize state-of-the-art robotics and a high-throughput neutralization assay to screen and identify monoclonal antibodies (mAbs) targeting the gH glycoproteins that display broad-spectrum properties to inhibit virus infection and dissemination. Subsequent biochemical characterization reveals that the mAbs bind to gH-trimer and gH-pentamer complexes and identify the antibodies’ epitope as an ‘antigenic hot spot’ critical for virus entry. The mAbs inhibit CMV infection at a post-attachment step by interacting with a highly conserved central alpha helix-rich domain. The platform described here provides the framework for development of effective CMV biologics and vaccine design strategies.

Date: 2016
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DOI: 10.1038/ncomms13627

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