Human Cytomegalovirus Latent Infection of Myeloid Cells Directs Monocyte Migration by Up-Regulating Monocyte Chemotactic Protein-1

Abstract

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 Gα 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.

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

“…CD34 1 progenitors, monocytes and granulocyte-macrophage progenitors, as well as some established myeloid cell lines, can be infected in culture allowing the maintenance of latent viral genomes which can then be reactivated by differentiation signals. 21,30,[35][36][37][45][46][47] However, it is clear that some experimental models using established cell lines do not appear to fully recapitulate all aspects of control of latency and reactivation observed in primary myeloid cells. 48 A totally quiescent viral genome during latent infection would clearly be the ideal way to avoid immune surveillance-if viral proteins are not expressed at all there would be no processing and presentation of viral antigens to specific T cells and, thus, latently infected cells would be ignored by the host immune response.…”

“…21 Subsequently, a comprehensive analysis of the secretome of experimentally latently infected CD34 1 progenitor cells identified changes in numerous secreted cellular proteins which are known to be involved in both the regulation of the immune response and chemoattraction. 61 In these studies, a latency-associated increase in the chemokine CCL8, perhaps counter-intuitively, resulted in the recruitment of CD4 1 T cells to latently infected cells.…”

“…3 For instance, during lytic infection, specific genes encoded by HCMV can directly modulate innate immune responses, such as the interferon (IFN) responses 5 and NK cell recognition. 7 The virus also encodes an immunosuppressive IL-10 homologue; 20,21 IL-10 is a powerful inhibitor of Th1 cytokines (such as IFN-c and IL-2) and also inhibits inflammatory cytokine production from monocytes and macrophages, which results in a decrease in surface MHC Class II expression and a reduction of presentation of antigen to CD4 1 T cells. 22 In addition, the virus also encodes proteins that act as receptors for host inflammatory cytokines, thereby reducing localized cytokine effectiveness by acting as cytokine sinks.…”

Human cytomegalovirus latency alters the cellular secretome, inducing cluster of differentiation (CD)4+T-cell migration and suppression of effector function

“…During experimental latent infection of granulocyte-macrophage progenitor cells (GMPs), CC chemokine ligand (CCL)2 [monocyte chemoattractant protein (MCP-1)] is up-regulated, and this enhances chemotaxis of cluster of differentiation (CD) 14 + monocytes (11). However, whether changes in secretion of other cytokines accompanies latent HCMV infection and what effect this has on chemotaxis and function of other immune cells, such as T cells and NK cells, which are known to play important roles in immunosurveillance of HCMV, is not known.…”

Mechanisms modulating immune clearance during human cytomegalovirus latency

“…This led to the discovery that virus-encoded IL-10 is secreted during latency and most likely reduces the effectiveness of CD4 + T-cell immune surveillance (17). The recognition that host-encoded chemokine MCP1 (CCL2) is secreted during latency to increase monocyte chemotaxis demonstrates the influence of virus on monocyte behavior (18). This growing understanding predicted that the impact of CMV latent infection extends beyond the infected cell to include the extracellular environment surrounding sites of latency.…”