Human cytomegalovirus latent infection of myeloid cells directs monocyte migration by up-regulating monocyte chemotactic protein-1.
Following primary infection, human cytomegalovirus (HCMV) establishes a latent infection in hematopoietic cells from which it reactivates to cause serious disease in immunosuppressed patients such as allograft recipients. HCMV is a common cause of disease in newborns and transplant patients and has also been linked with vascular diseases such as primary and post-transplant arteriosclerosis. A major factor in the pathogenesis of vascular disease is the CC chemokine MCP-1. In this study, we demonstrate that granulocyte macrophage progenitors (GMPs) latently infected with HCMV significantly increased expression of MCP-1 and that this phenotype was dependent on infection with viable virus. Inhibitors of a subset of G(alpha) proteins and PI3K inhibited the up-regulation of MCP-1 in latently infected cultures, suggesting that the mechanism underlying this phenotype involves signaling through a G-protein coupled receptor. In GMPs infected with the low passage viral strain Toledo, up-regulated MCP-1 was restricted to a subset of myeloid progenitor cells expressing CD33, HLA-DR, and CD14 but not CD1a, CD15, or CD16, and the increase in MCP-1 was sufficient to enhance migration of CD14(+) monocytes to latently infected cells. Latent HCMV-mediated up-regulation of MCP-1 provides a mechanism by which HCMV may contribute to vascular disease during the latent phase of infection or facilitate dissemination of virus upon reactivation from latency.
Stern
J Lewis
JL
Centre for Virus Research, Westmead Millennium Institute and the University of Sydney, Westmead, NSW, Australia.
Slobedman
Barry
B
D002465:Cell Movement / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003587:Cytomegalovirus / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000276:immunology*; D005434:Flow Cytometry; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000821:virology; D006801:Humans; D009000:Monocytes / Q000378:metabolism / Q000821:virology; D022423:Myeloid Cells / Q000378:metabolism / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D017735:Virus Latency / Q000502:physiology*
D018932:Chemokine CCL2; D044385:GTP-Binding Protein alpha Subunits