Human cytomegalovirus persistence and latency in endothelial cells and macrophages

doi:10.1016/S1369-5274(02)00334-X

Current Opinion in Microbiology

Volume 5, Issue 4, 1 August 2002, Pages 403-407

https://doi.org/10.1016/S1369-5274(02)00334-X Get rights and content

Abstract

Human cytomegalovirus (HCMV) is a clinically significant herpes virus that maintains a lifelong infection in the host. HCMV infection of endothelial cells and macrophages plays an important role in the establishment of latency and persistence, which appears critical for the maintenance of HCMV within the host. HCMV infection is profoundly influenced by endothelial cell origin and the specific pathway of macrophage differentiation. Multiple HCMV genes appear to be involved in enabling virus replication in these two cell types. Although the specific HCMV gene(s) mediating endothelial and macrophage tropism are unclear, a number of genetic determinants required for replication in these two cell types have been identified in the closely related murine cytomegalovirus (MCMV) mouse model, revealing novel mechanisms of virus tropism. This review focuses on recent advances in the understanding of HCMV replication in endothelial cells and macrophages, and the viral determinants that mediate replication in these two important cell types.

Introduction

Human cytomegalovirus (HCMV) is a ubiquitous herpes virus that establishes a life-long infection after initial exposure, which occurs primarily in childhood. Although the majority of HCMV infections results in subclinical disease in healthy individuals, the virus is a significant pathogen in immunocompromised transplant patients and in neonates [1]. Histological analyses of tissues obtained from patients with HCMV disease have identified infected cells in virtually all organs. Infection occurs in a variety of cell types, including macrophages, endothelial cells, epithelial cells, fibroblasts, stromal cells, neuronal cells, smooth muscle cells and hepatocytes 2., 3., 4.. Endothelial cells and macrophages have been implicated as sites of HCMV persistence and latency, and replication of HCMV in these two cell types is believed to play an important role in enabling the virus to maintain a life-long infection within the host. In addition, a number of studies indicate that HCMV infection may modulate interactions between these two cell types to facilitate the spread of infection throughout the host 5., 6.. This review will focus on recent advances in our understanding of HCMV replication in endothelial cells and macrophages, and the viral determinants that mediate replication in these two important cell types.

Section snippets

Growth of HCMV in endothelial cells

Endothelial cells are considered to be important reservoirs of HCMV in the host. Examination of the parameters of HCMV growth in this cell type has been the subject of intensive study in recent years. Results from these studies have shown that the specific origin of the endothelial cell has a profound effect on the characteristics of HCMV infection. Studies, in our laboratory, that compare HCMV infection in brain microvascular endothelial cells (BMVECs) with that in aortic macrovascular

Determinants of HCMV endothelial-cell tropism

HCMV replication in endothelial cells is also influenced by viral strain, suggesting that specific viral gene(s) are required for efficient replication in this cell type 8., 9., 10.. A number of early studies observed a loss of endothelial tropism of clinical HCMV isolates after passage in human fibroblasts, a cell type commonly used for production of high-titer virus stocks. Recent studies investigating the phenotypic changes associated with HCMV passage in fibroblasts compared to endothelial

Growth of HCMV in macrophages

A major focus of our laboratory has been the generation and characterization of monocyte-derived macrophage (MDM) culture systems to study HCMV replication. These studies have shown that CD14⁺ monocytes are sites of HCMV latency in vivo, and that the particular differentiation pathway used for the production of MDM has a dramatic effect on the characteristics of HCMV infection and reactivation 18., 19., 20•.. We have developed a MDM system that is permissive to HCMV replication and enables

Determinants of HCMV macrophage cell tropism

Currently, viral genes associated with growth in MDMs have been identified only in the MCMV system. In addition to M45 (see earlier), M140 and M141 gene products (pM140 and pM141, respectively) have been shown to be required for normal in vitro replication in macrophages 14••., 31•., 32., 33.. Replication in macrophages of MCMV mutants that lack these genes was reduced, but not totally eliminated, suggesting that other MCMV genes are involved in viral replication in MDMs. In animal studies,

Conclusions

Endothelial cells and macrophages have been implicated as sites of HCMV persistence and latency, and replication of HCMV in these two cell types is believed to play an important role in enabling the virus to maintain a life-long infection within the host. The ability of HCMV to produce a persistent long-term productive infection in AECs suggests that AECs may represent a site of persistence within the host. The capacity to reactivate HCMV from latently infected CD14⁺ monocytes identifies the

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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Differential mRNA Expressions in HCMV infected HUVECs*
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The aim was to identify the gene expressions of human cytomegalovirus (HCMV)-infected human umbilical vein endothelial cells (HUVECs) and to study its possible pathogenic mechanism on atherosclerosis using microarray technology.
The gene expression differences in HCMV AD169 strain-infected HUVECs were studied by the microarray technology to explore the potential molecular mechanism of HCMV infection. The qPCRs were performed to verify the transcriptome results.
A total of 2,583 differentially expressed genes, including 407 down-regulated genes and 2,176 up-regulated genes, were detected by the systematic bioinformatics analysis. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the significantly differentially expressed genes were mainly involved in regulating protein kinase activity, inflammatory response, ubiquitination, protein phosphorylation, cell metabolism, and exosomes, among which 12 genes had significant changes and were screened by protein-protein interaction (PPI) analysis and verified by qPCR. The experimental qPCR results were consistent with the microarray results.
The GO and KEGG analyses revealed that the regulation of protein kinase activity, inflammatory response, ubiquitination, protein phosphorylation, and cell metabolism played important roles in the process of endothelial cell infection. Furthermore, 12 genes were involved in the process of HCMV infection of endothelial cells and contributed to the current understanding of the infection and pathogenic mechanisms of atherosclerosis.
Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment
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Citation Excerpt :
Replication and latency are maintained through a delicate balance between productive (lytic) and non-productive (latent) phases of viral life cycle. T-cell–mediated immune control, as well as changes in the differentiation/activation state of cells harboring integrated viral genome, controls transition between these states [14,15]. While isolated reactivation events occur intermittently in the immunocompetent host without causing clinical symptoms [16], immunosuppression may result in reactivation and lead to viremia and/or virus-associated systemic or end-organ disease [17].
Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.
Curcumin inhibits the formation of atherosclerosis in ApoE<sup>−/−</sup> mice by suppressing cytomegalovirus activity in endothelial cells
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Citation Excerpt :
VECs are considered to be the target cell of HCMV infection [9]. The replication of CMV in VECs is the key to viral sustained infection and transmission, and is the most direct cause of endothelial dysfunction, which leads to proliferation of vascular smooth muscle cells and vascular dysfunction, and finally leads to the occurrence of AS [13]. In the present study, it was demonstrated that CMV infection accelerated AS progression by viral replication and proliferation, increasing the intracellular ROS overproduction, increasing the release of inflammatory cytokines, up-regulating the level of HMGB1-TLRS-NF-κB signaling pathway-related protein both in vitro and in vivo experiments.
Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells.
This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro.
Cur (0.5, 1, and 2 μM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE^−/− mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo.
As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments.
This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.
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ReviewHuman cytomegalovirus persistence and latency in endothelial cells and macrophages

Abstract

Introduction

Section snippets

Growth of HCMV in endothelial cells

Determinants of HCMV endothelial-cell tropism

Growth of HCMV in macrophages

Determinants of HCMV macrophage cell tropism

Conclusions

References and recommended reading

Virus Res

Cell

Blood

Blood

Blood

Virology

Cytomegalovirus

Detection of human cytomegalovirus in peripheral blood lymphocytes in a natural infection

Science

Fibroblasts, epithelial cells, endothelial cells and smooth muscle cells are major targets of human cytomegalovirus infection in lung and gastrointestinal tissues

J Gen Virol

Definition of a subset of human peripheral blood mononuclear cells that are permissive to human cytomegalovirus infection

J Virol

Bidirectional transmission of infectious cytomegalovirus between monocytes and vascular endothelial cells: an in vitro model

J Infect Dis

Cytomegalovirus-mediated modulation of adhesion molecule expression by human arterial and microvascular endothelial cells

Transplantation

Human cytomegalovirus persistently infects aortic endothelial cells

J Virol

Efficient lytic infection of human arterial endothelial cells by human cytomegalovirus strains

J Virol

Modification of human cytomegalovirus tropism through propagation in vitro is associated with changes in the viral genome

J Gen Virol

Two clinical isolates and the Toledo strain of cytomegalovirus contain endothelial cell tropic variants that are not present in the AD169, Towne, or Davis strains

J Med Virol

Review
Human cytomegalovirus persistence and latency in endothelial cells and macrophages