Rapamycin does not inhibit human cytomegalovirus reactivation from dendritic cells in vitro

Thomas E Glover,Matthew B Reeves,Verity G Kew

doi:10.1099/vir.0.066332-0

Abstract

Human cytomegalovirus (HCMV) infection and reactivation are a major cause of morbidity in immune-suppressed patients. Interestingly, epidemiological studies have shown that patients administered the mammalian target of rapamycin (mTOR) inhibitor, sirolimus (rapamycin), exhibit more favourable outcomes, suggestive of activity against HCMV in vivo. Given its relative lack of activity against lytic infection, it is postulated that rapamycin inhibits HCMV reactivation. Here, we showed that rapamycin administered acutely or chronically has little impact on induction of immediate early (IE) gene expression in experimentally latent dendritic cells or cells from naturally latent individuals. Furthermore, we extended these observations to include other inhibitors of mTORC1 and mTORC 2, which similarly have minimal effects on induction of IE gene expression from latency. Taken together, these data suggest that favourable outcomes associated with sirolimus are attributable to indirect effects that influence HCMV reactivation, rather than a direct mechanistic action against HCMV itself.

Highlights

Human cytomegalovirus (HCMV) infection and reactivation are a major cause of morbidity in immune-suppressed patients
Epidemiological studies have shown that patients administered the mammalian target of rapamycin inhibitor, sirolimus, exhibit more favourable outcomes, suggestive of activity against HCMV in vivo
Targets of rapamycin (Tor1 and Tor2) were originally identified as yeast proteins sensitive to a naturally occurring antifungal agent expressed by Streptomyces hygroscopicus (Heitman et al, 1991; Vezina et al, 1975), and subsequent studies revealed a mammalian target active against the mammalian target of rapamycin (mTOR) complex 1 arm (Heitman et al, 1991; Sabatini et al, 1994). mTOR is a serine/threonine kinase controlling a range of cellular functions, including cell growth, proliferation and survival and affecting transcription and protein synthesis (Lamming et al, 2013)

Summary

Short Communication

Rapamycin does not inhibit human cytomegalovirus reactivation from dendritic cells in vitro. We showed that rapamycin administered acutely or chronically has little impact on induction of immediate early (IE) gene expression in experimentally latent dendritic cells or cells from naturally latent individuals We extended these observations to include other inhibitors of mTORC1 and mTORC 2, which have minimal effects on induction of IE gene expression from latency. Within 12 h, phosphorylation of 4E-BP1 becomes insensitive to rapamycin, as shown by Kudchodkar et al (2004) Reconciling these data with improved prognosis regarding HCMV infection for patients immunosuppressed with sirolimus led to the proposal that sirolimus abrogates HCMV reactivation and disease in vivo by preventing reactivation of HCMV IE gene expression (Marty et al, 2007).

Reactivation of HCMV in DCs independent of rapamycin

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Relative IE expression

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