Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology


Autoři: Jihye Park aff001;  Kevin Sean Gill aff001;  Ali Asghar Aghajani aff001;  Jeremiah Dallas Heredia aff001;  Hannah Choi aff001;  Adam Oberstein aff002;  Erik Procko aff001
Působiště autorů: Department of Biochemistry, University of Illinois, Urbana, Illinois, United States of America aff001;  Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, United States of America aff002;  Cancer Center at Illinois (CCIL), University of Illinois, Urbana, Illinois, United States of America aff003
Vyšlo v časopise: Engineered receptors for human cytomegalovirus that are orthogonal to normal human biology. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1008647
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008647

Souhrn

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.

Klíčová slova:

Cell binding – Cytomegalovirus infection – Flow cytometry – Human cytomegalovirus – Mutagenesis – Nonsense mutation – Signal processing – Substitution mutation


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