title: Glucocorticosteroids trigger reactivation of human cytomegalovirus from latently infected myeloid cells and increase the risk for HCMV infection in D+R+ liver transplant patients.
abstract: Graft rejection in transplant patients is managed clinically by suppressing T-cell function with immunosuppressive drugs such as prednisolone and methylprednisolone. In such immunocompromised hosts, human cytomegalovirus (HCMV) is an important opportunistic pathogen and can cause severe morbidity and mortality. Currently, the effect of glucocorticosteroids (GCSs) on the HCMV life cycle remains unclear. Previous reports showed enhanced lytic replication of HCMV in vitro in the presence of GCSs. In the present study, we explored the implications of steroid exposure on latency and reactivation. We observed a direct effect of several GCSs used in the clinic on the activation of a quiescent viral major immediate-early promoter in stably transfected THP-1 monocytic cells. This activation was prevented by the glucocorticoid receptor (GR) antagonist Ru486 and by shRNA-mediated knockdown of the GR. Consistent with this observation, prednisolone treatment of latently infected primary monocytes resulted in HCMV reactivation. Analysis of the phenotype of these cells showed that treatment with GCSs was correlated with differentiation to an anti-inflammatory macrophage-like cell type. On the basis that these observations may be pertinent to HCMV reactivation in post-transplant settings, we retrospectively evaluated the incidence, viral kinetics and viral load of HCMV in liver transplant patients in the presence or absence of GCS treatment. We observed that combination therapy of baseline prednisolone and augmented methylprednisolone, upon organ rejection, significantly increased the incidence of HCMV infection in the intermediate risk group where donor and recipient are both HCMV seropositive (D+R+) to levels comparable with the high risk D+R- group.
authors.affiliation: Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Damme
authors.affiliation: Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sauviller
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: Betty
authors.initials: B
authors.lastname: Lau
authors.affiliation: Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Kesteleyn
authors.affiliation: Division of Infection and Immunity (Royal Free Campus), University College London, Rowland Hill Street, Hampstead, London NW3 2QG, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Griffiths
authors.affiliation: Sheila Sherlock Liver Centre, Royal Free NHS Trust, Hampstead, London NW3 2QG, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Burroughs
authors.affiliation: Department of Microbial and Cellular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.|Division of Infection and Immunity (Royal Free Campus), University College London, Rowland Hill Street, Hampstead, London NW3 2QG, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Emery
authors.affiliation: Department of Medicine, University of Cambridge, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Sinclair
authors.affiliation: Janssen Infectious Diseases BVBA, Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Marnix
authors.initials: M
authors.lastname: Van Loock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D003141:Communicable Diseases / Q000378:metabolism / Q000821:virology; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000821:virology; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D016867:Immunocompromised Host / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000821:virology*; D016031:Liver Transplantation / Q000379:methods; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D022423:Myeloid Cells / Q000378:metabolism / Q000821:virology*; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D019562:Viral Load / Q000502:physiology; D014775:Virus Activation / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology*; D055815:Young Adult
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid