Biomaterial Database

Cytomegalovirus US28 regulates cellular EphA2 to maintain viral latency. 2022

Amanda B Wass, and Benjamin A Krishna, and Laura E Herring, and Thomas S K Gilbert, and Masatoshi Nukui, and Ian J Groves, and Abigail L Dooley, and Katherine H Kulp, and Stephen M Matthews, and Daniel M Rotroff, and Lee M Graves, and Christine M O'Connor

Department of Genomic Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Cytomegalovirus (CMV) reactivation from latency following immune dysregulation remains a serious risk for patients, often causing substantial morbidity and mortality. Here, we demonstrate the CMV-encoded G protein-coupled receptor, US28, in coordination with cellular Ephrin receptor A2, attenuates mitogen-activated protein kinase signaling, thereby limiting viral replication in latently infected primary monocytes. Furthermore, treatment of latently infected primary monocytes with dasatinib, a Food and Drug Association-approved kinase inhibitor used to treat a subset of leukemias, results in CMV reactivation. These ex vivo data correlate with our retrospective analyses of the Explorys electronic health record database, where we find dasatinib treatment is associated with a significant risk of CMV-associated disease (odds ratio 1.58, P = 0.0004). Collectively, our findings elucidate a signaling pathway that plays a central role in the balance between CMV latency and reactivation and identifies a common therapeutic cancer treatment that elevates the risk of CMV-associated disease.