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.

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

“…In the absence of HIV-1, induction of replicating CMV has been shown to occur with the terminal differentiation of monocytes to myeloid dendritic cells, 49 and in vitro studies have demonstrated that monocyte to macrophage differentiation leads to production of infectious virus. [50][51][52] If HIV-1 infection activates monocytes and macrophages, 53 it is likely that CMV could be reactivated and replicate leading to an inflammatory response. In our study the association of CMV IgG with sCD14 within the HIV-1 viremic group, which was not present in the HIV-uninfected group, suggests that coinfection and long-term interaction of HIV-1 and CMV may lead to the development of serious non-AIDS events.…”

Glucocorticoids facilitate the transcription from the human cytomegalovirus major immediate early promoter in glucocorticoid receptor- and nuclear factor-I-like protein-dependent manner

“…Recently, it was reported that glucocorticoid plays a role in the HCMV kinetics of latency and reactivation, and that treatment with these compounds may increase the probability of HCMV-related complications post transplantation [11]. Our findings strongly suggest that glucocorticoid metabolism is deeply involved in HCMV life cycle and its related diseases in human body.…”

“…Next to clarify whether the DEXmediated transcriptional activation of the MIE promoter is dependent on GR, we examined the effect of RU486, a GR antagonist, on DEX-mediated transcriptional activation (Fig. 3F) [11]. In cells transfected with pMIEP-Luc-210, the DEX-mediated increase of the luciferase activity was suppressed by RU486.…”

“…These results suggested that DEX treatment facilitates HCMV virus production through activation of the MIE gene expression. Recently, it was reported that glucocorticoids trigger reactivation of HCMV from HCMV-latently infected myeloid cells and increases the incidence of HCMV infection in liver transplant patients when both donor and recipient are HCMV seropositive [11]. Furthermore, it is suggested that HCMV infection in the third trimester of pregnant women is probably due to elevation of the plasma hydroxycorticoid level [12].…”

Frequent occurrence of therapeutically reversible cmv-associated encephalopathy during radiotherapy of the brain.

“…23 Especially dexamethasone has been shown to cause CMV replication in vitro 24 and in vivo. 25 Cytomegalovirus is considered to be controlled by lymphocytes. 26,27 While the virus inhibits the function of T cells, 21 corticosteroids are lympholytic themselves, 28 likely increasing the risk for CMV reactivation.…”