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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.
Highlights
Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause lifethreatening disease
It was previously shown that F49A-Fusion toxin proteins (FTPs) is able to kill fibroblast cells that were lytically infected with HCMV46
F49A-FTP was able to kill human foreskin fibroblasts (HFFs) infected with wild-type Titan HCMV but not the corresponding US28-deletion virus (Fig. 1)
Summary
Reactivation of human cytomegalovirus (HCMV) in transplant recipients can cause lifethreatening disease. One site of latent carriage is in cells of the early myeloid lineage that includes CD34 þ progenitor cells and CD14 þ monocytes[4] In these latently infected cells, maintenance of viral genome is associated with expression of a relatively small number of latency-associated viral genes and no infectious virus is produced. It is clear that, in healthy HCMV-positive donor cells, differentiation of CD14 þ monocytes and CD34 þ progenitors to dendritic cells and macrophages triggers virus reactivation from latency[3,6,7,8] and that this differentiation-dependent reactivation of latent virus in the myeloid lineage is mediated by changes in post-translational modification of histones around the viral MIEP (major immediate-early promoter) This drives viral major immediate-early (IE) gene expression, resulting in reactivation of the viral lytic gene cascade and the production of infectious virions[7]. The functions of many of these latency-associated gene products are becoming better established, their roles in latency are still unclear
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