Abstract
A trimeric glycoprotein complex on the surface of human cytomegalovirus (HCMV) binds to platelet-derived growth factor (PDGF) receptor α (PDGFRα) to mediate host cell recognition and fusion of the viral and cellular membranes. Soluble PDGFRα potently neutralizes HCMV in tissue culture, and its potential use as an antiviral therapeutic has the benefit that any escape mutants will likely be attenuated. However, PDGFRα binds multiple PDGF ligands in the human body as part of developmental programs in embryogenesis and continuing through adulthood. Any therapies with soluble receptor therefore come with serious efficacy and safety concerns, especially for the treatment of congenital HCMV. Soluble virus receptors that are orthogonal to human biology might resolve these concerns. This engineering problem is solved by deep mutational scanning on the D2-D3 domains of PDGFRα to identify variants that maintain interactions with the HCMV glycoprotein trimer in the presence of competing PDGF ligands. Competition by PDGFs is conformation-dependent, whereas HCMV trimer binding is independent of proper D2-D3 conformation, and many mutations at the receptor-PDGF interface are suitable for functionally separating trimer from PDGF interactions. Purified soluble PDGFRα carrying a targeted mutation succeeded in displaying wild type affinity for HCMV trimer with a simultaneous loss of PDGF binding, and neutralizes trimer-only and trimer/pentamer-expressing HCMV strains infecting fibroblasts or epithelial cells. Overall, this work makes important progress in the realization of soluble HCMV receptors for clinical application.
Highlights
Human cytomegalovirus (HCMV; or human herpesvirus 5, HHV-5) is a ubiquitous pathogen that has infected most of the global adult population, and typically causes asymptomatic infections [1,2]
Human cytomegalovirus (HCMV) causes severe disease in transplant recipients and immunocompromised patients, and infections in a fetus or neonate are responsible for life-long neurological defects
Cell entry is in part mediated by a trimeric glycoprotein complex on the viral surface, which binds tightly to the host receptor plateletderived growth factor receptor α (PDGFRα)
Summary
Human cytomegalovirus (HCMV; or human herpesvirus 5, HHV-5) is a ubiquitous pathogen that has infected most of the global adult population, and typically causes asymptomatic infections [1,2]. Antivirals have not been approved by the U.S Food and Drug Administration for routine use in the treatment of congenital HCMV where there are unique concerns regarding toxicity, and drug resistance is widely reported [20]. Faced with this reality, the American College of Obstetricians and Gynecologists does not make any specific recommendations for counseling or treating pregnant women for the prevention of HCMV [21]
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