CMV Late Phase‐Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages

• Published in: American journal of transplantation Vol. 12; no. 6; pp. 1458 - 1468
• Main Authors: Poglitsch, M., Weichhart, T., Hecking, M., Werzowa, J., Katholnig, K., Antlanger, M., Krmpotic, A., Jonjic, S., Hörl, W. H., Zlabinger, G. J., Puchhammer, E., Säemann, M. D.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.06.2012; Wiley
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; beta -Interferon; Biological and medical sciences; Blotting, Western; Cell activation; Cells, Cultured; Cytokines; Cytomegalovirus; Cytomegalovirus - physiology; Data processing; Enzyme-Linked Immunosorbent Assay; Human cytomegalovirus; Humans; Immunohistochemistry; Infection; Infectious diseases; Inflammation; interferon‐beta; Macrophages; Macrophages - virology; MAP kinase; Medical sciences; Membrane Fusion; Molecular modelling; Myeloid cells; Organs; Pathogens; Pharmacology. Drug treatments; Polymerase Chain Reaction; pp65 protein; Protein biosynthesis; protein synthesis; Proteins; Rapamycin; renal transplantation; Replication; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the urinary system; TOR protein; TOR Serine-Threonine Kinases - metabolism; Viral diseases; Virus Replication; Antineoplastic agent; Sirolimus; renal transplantation; Activation; Late-phase; Homotransplantation; Betaherpesvirinae; Essential; Kidney; Macrocycle; Human cytomegalovirus; macrophages; Surgery; interferon-beta; Graft; Protein synthesis inhibitor; Human; Opportunistic infection; Cytomegalovirus; Herpesviridae; Cytokine; Lactone; Macrolide; Infection; Virus; Antibiotic; Treatment; Urinary system; Viral disease; Beta interferon; Mammalian target of rapamycin; Replication; Immunosuppressive agent; Antibacterial agent; Macrophage; Kidney transplantation; rapamycin
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2012.04002.x

Human cytomegalovirus (CMV) remains one of the most important pathogens following solid‐organ transplantation. Mounting evidence indicates that mammalian target of rapamycin (mTOR) inhibitors may decrease the incidence of CMV infection in solid‐organ recipients. Here we aimed at elucidating the molecular mechanisms of this effect by employing a human CMV (HCMV) infection model in human macrophages, since myeloid cells are the principal in vivo targets of HCMV. We demonstrate a highly divergent host cell permissiveness for HCMV with optimal infection susceptibility in M2 but not M1 polarized macrophages. Employing an ultrahigh purified HCMV stock we observed rapamycin‐independent viral entry and induction of IFN‐β transcripts, but no proinflammatory cytokines or mitogen‐activated protein kinases and mTOR activation early after infection. However, in the late infection phase, sustained mTOR activation was observed in HCMV‐infected cells and was required for efficient viral protein synthesis including the viral late phase proteins pUL‐44 and pp65. Accordingly, rapamycin strongly suppressed CMV replication 3 and 5 days postinfection in macrophages. In conclusion, these data indicate that mTOR is essential for virus replication during late phases of the viral cycle in myeloid cells and might explain the potent anti‐CMV effects of mTOR inhibitors after organ transplantation. The authors demonstrate that human cytomegalovirus efficiently infects human macrophages without a concomitant inflammatory response and further utilizes mTOR for successful viral replication, a process that can be fully suppressed by rapamycin.