Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein.
Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause life-threatening disease. Consequently, for transplant recipients, killing latently infected cells could have far-reaching clinical benefits. In vivo, myeloid cells and their progenitors are an important site of HCMV latency, and one viral gene expressed by latently infected myeloid cells is US28. This viral gene encodes a cell surface G protein-coupled receptor (GPCR) that binds chemokines, triggering its endocytosis. We show that the expression of US28 on the surface of latently infected cells allows monocytes and their progenitor CD34+ cells to be targeted and killed by F49A-FTP, a highly specific fusion toxin protein that binds this viral GPCR. As expected, this specific targeting of latently infected cells by F49A-FTP also robustly reduces virus reactivation in vitro. Consequently, such specific fusion toxin proteins could form the basis of a therapeutic strategy for eliminating latently infected cells before haematopoietic stem cell transplantation.
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB20QQ, UK.
B A
BA
Krishna
Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
K
K
Spiess
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB20QQ, UK.
E L
EL
Poole
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB20QQ, UK.
B
B
Lau
Department of Infectious Diseases, Robert Koch Institute, Nordufer 20, Berlin 13353, Germany.|Department of Pediatric Oncology/Hematology/SCT, Charité-Universitätsmedizin, Berlin 13353, Germany.
S
S
Voigt
Section for Virology, The National Veterinary Institute, Technical University of Denmark, Frederiksberg DK-1870, Denmark.
T N
TN
Kledal
Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark.
M M
MM
Rosenkilde
Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB20QQ, UK.
J H
JH
Sinclair
D018952:Antigens, CD34 / Q000276:immunology; D016923:Cell Death; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000302:isolation & purification* / Q000472:pathogenicity; D004197:Disease Reservoirs; D004705:Endocytosis; D005814:Genes, Viral; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D009000:Monocytes / Q000276:immunology / Q000821:virology; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000276:immunology / Q000821:virology; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014775:Virus Activation; D017735:Virus Latency
D018952:Antigens, CD34; D018925:Chemokines; D018950:Lipopolysaccharide Receptors; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; C411191:US28 receptor, Cytomegalovirus; D014764:Viral Proteins