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, Domenico Tortorella

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish
Article number13627
JournalNature Communications
Volume7
DOIs
StatePublished - 14 Dec 2016

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