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Targeting the latent cytomegalovirus reservoir with an antiviral fusion toxin protein.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Krishna, BA 
Spiess, K 
Poole, EL 
Lau, B 
Voigt, S 

Abstract

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.

Description

Keywords

Antigens, CD34, Cell Death, Cells, Cultured, Chemokines, Cytomegalovirus, Disease Reservoirs, Endocytosis, Genes, Viral, Hematopoietic Stem Cell Transplantation, Humans, Lipopolysaccharide Receptors, Monocytes, Receptors, Chemokine, Recombinant Fusion Proteins, Stem Cells, Viral Load, Viral Proteins, Virus Activation, Virus Latency

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

8

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/K021087/1)
Medical Research Council (G0701279)
MRC (MC_PC_14116 v2)
Wellcome Trust (099790/Z/12/Z)