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Annals of Clinical & Laboratory Science 34:123-130 (2004)
© 2004 Association of Clinical Scientists

Review

CMV Escapes!

M. Kent Froberg
Department of Pathology and Laboratory Medicine, School of Medicine, University of Minnesota–Duluth, Duluth, Minnesota

Address correspondence to M. Kent Froberg, DVM, MD, Department of Pathology and Laboratory Medicine, University of Minnesota–Duluth School of Medicine, 1035 University Drive, Duluth, MN 55812, USA; tel 218 726 7223; fax 218 726 7559; e-mail kfroberg{at}d.umn.edu.


   Abstract
Top
 Abstract
Introduction
 Primary infection/latency
 Apoptosis/mitogenesis
 Blocking antigen presentation
 G Protein-coupled receptor...
 Lipid metabolism and CMV
 Conclusions
 References
 
Cytomegalovirus (CMV) is an opportunistic pathogen that establishes life-long latent infection without clinical disease in immunocompetent individuals, but can cause severe illness in newborns, transplant recipients, and patients with HIV. CMV has evolved complex molecular mechanisms to avoid host immune detection and destruction. Collectively these mechanisms have been termed "immunoevasion" or "escapology." Perhaps the most essential mechanism of virus survival within the host is latency, a form of reversible nonproductive infection of host cells by replication-competent virus. During periods of active virus replication, however, there are multiple strategies by which CMV evades host defenses. These include methods referred to as camouflage, which aid the virus in hiding from immune defenses, and those referred to as sabotage, whereby the virus disrupts or manipulates host inflammatory or immune responses. The ultimate pathogen survival strategy, host cell transformation, has been demonstrated in vitro for CMV, but to date has not been demonstrated in vivo. This review surveys the current literature on CMV immunoevasion and suggests a paradigm whereby CMV survives host defenses and contributes to atherogenesis.

(received 20 November 2003; accepted 28 November 2003)

Keywords: cytomegalovirus, escapology, immunoevasion, cytokines, atherosclerosis


   Introduction
Top
 Abstract
 Introduction
Primary infection/latency
 Apoptosis/mitogenesis
 Blocking antigen presentation
 G Protein-coupled receptor...
 Lipid metabolism and CMV
 Conclusions
 References
 
Cytomegalovirus is a ubiquitous beta-herpesvirus which causes most adult persons to become sero-positive by the age of 35 yr [1]. Most CMV infectons are mild or asymptomatic. However, like other herpes viruses, CMV establishes life-long latent infection with the potential of causing clinical disease following reactivation. Acute clinical illness is most often seen in neonates, solid organ or bone marrow transplant patients, or patients with AIDS. While the extremes of infection, latent virus without clinical disease vs life threatening disease in immunocompromised patients, are well recognized, the in vivo battle where neither virus or host appears to win, is less clearly defined.

There is substantial evidence that CMV infection plays a role in atherosclerosis, restenosis after angioplasty, and the de novo atherosclerosis that may arise following heart transplantation [2–5]. Since atherosclerosis is a chronic inflammatory disease of blood vessel walls, and latent CMV infection occurs in tissues at these sites, one may reason that reactivation of the virus could contribute to the chronic inflammatory process and exacerbate or accelerate vascular lesions. Understanding how CMV survives in these tissues and the mechanisms of reactivation and immunoevasion could establish the extent to which CMV contributes to atherogenesis and could lead to new methods to suppress the reactivation of CMV and its accompanying inflammatory cascade.

CMV has a large genome compared to many viruses and appears to have acquired several host genes over a long period of co-evolution with its host [6–9]. Many of these genes allow CMV to modulate both the host immune response and virus replication in the face of host cell mitogenic or proinflammatory activation. Collectively these genes and proteins have been termed "immunoevasins" and the overall process termed viral "escapology" [7,8]. CMV avoids immune detection through camouflage, the art of hiding from host defenses, as well as subverting the immune system by sabotage, the synthesis of molecules that disrupt or manipulate host immune/inflammatory responses. Virally produced molecules involved in these processes include cytokine homologs (virokines), soluble cytokine scavengers that sequester free chemokines, and cell–surface receptor homologs (viroceptors) [7]. Most studies of CMV escapology have been conducted on human CMV (hCMV) or murine CMV (mCMV) using in vitro techniques. In combination, these immunoevasive activities may allow CMV to contribute to atherosclerotic disease by surviving the onslaught of host defenses and contributing to chronic inflammation during periods of reactivation. Herein, we review the numerous and complex ways in which CMV interacts with host defenses and we attempt to formulate a hypothesis to define CMV’s role in atherogenesis.


   Primary infection/latency
Top
 Abstract
 Introduction
 Primary infection/latency
Apoptosis/mitogenesis
 Blocking antigen presentation
 G Protein-coupled receptor...
 Lipid metabolism and CMV
 Conclusions
 References
 
Like other herpes viruses, CMV establishes life-long latent infection once the host is exposed [10,11]. Replication is controlled by three groups of genes termed immediate early (IE), early (E), and late (L) phase genes. IE genes are under the control of the major IE promoter (MIEP), which controls the expression of two genetic elements IE-1 and IE-2. IE genes, in turn, regulate expression of E and L genes. MIEP is a potent transactivator of several viral and host genes and along with IE genes appears to play an important role in viral pathogenesis [12]. IE gene products appear to be particularly important in the proinflammatory response seen in CMV infection and may (a) increase levels of adhesion molecules such as ICAM, (b) increase production of cytokines such as IL-1 and TNF-{alpha}; (c) upregulate several chemokines like MCP-1, MIP-1ß, RANTES, and IL-8; and (d) stimulate expression of growth factors and mitogens including IL-6, TGF-ß and GM-CSF [13–16].

Control of latency is defined as the reversible non-productive infection of cells by replicative-competent virus and probably presents the best way for a virus to camouflage itself from immune detection. It implies that either no or relatively few viral genes are expressed and that no virions are produced. CMV may infect and be transferred between monocytes, endothelial cells, and smooth muscle cells, which are all central to atherogenesis. These cells may be activated by CMV infection and produce proinflammatory cytokines and chemokines that attract inflammatory cells to sites of vascular injury, adhesion molecules that enhance binding of inflammatory cells to the vessel wall, mitogens that may stimulate replication of smooth muscle cells or fibroblasts, and agents that stimulate lipid oxidation and free radical accumulation in damaged vascular walls [17–19]. The exact mechanisms of latency and reactivation of CMV are not well understood, but recent studies suggest reactivation may be more common than previously believed and may occur with minor stress-related events such as work overload, the occurrence of oral herpes, or alcohol ingestion [20]. These events, which are relatively common in many patients, could provide the CMV virus with multiple opportunities to contribute to the chronic inflammatory process we know as atherogenesis.


   Apoptosis/mitogenesis
Top
 Abstract
 Introduction
 Primary infection/latency
 Apoptosis/mitogenesis
Blocking antigen presentation
 G Protein-coupled receptor...
 Lipid metabolism and CMV
 Conclusions
 References
 
A potential way by which CMV may prevent virions from being exposed to host defenses would be to reduce apoptosis of CMV infected cells, thus limiting the amount of extra-cellular virus released from these cells. Virally infected or damaged cells may undergo apoptosis as a host defense mechanism to maintain stable cell populations and perhaps limit tissue injury or oncogenesis. Apoptotic cells are present in atherosclerotic lesions and may play a significant role in restenosis following coronary angioplasty [3,4,21]. Angioplasty induces excessive smooth muscle cell proliferation, with rapid restenosis occurring in 25–50% of patients undergoing coronary angioplasty [4]. CMV appears to block TNF-{alpha} induced apoptosis through the action of IE1 and IE2 genes [22–25]. p53 is a nucleoprotein that directs cells to programmed cell death, and the hCMV protein IE2-84 binds to and inhibits p53 transcriptional activity. p53 is sequestered within the cytoplasm of CMV-infected human endothelial cells in vitro [26]. By inhibiting apoptosis, CMV may contribute to the excessive proliferation of SMC seen in restenosis.

CMV genes also induce proliferation of host cells and cause transformation of several cell lines in vitro. The MIEP of CMV transactivates NF{kappa}B, which in turn activates several host and viral genes enhancing viral replication and infectivity [27,28]. Indeed, inflammation and activation of macrophages can lead to upregulation of PGE2, TNF-{alpha} and IL-1ß, which can alone or synergistically upregulate MIEP in vitro [29,30]. Thus, it is possible that activation of macrophages can lead to reactivation of CMV from the latent state facilitating viral pathogenesis within atherosclerotic lesions. Other factors that appear to activate CMV include reactive oxygen species (ROS) and nitric oxide (NO) [18,19, 31]. ROS are generated during atherogenesis, and NO is produced by activated macrophages and endothelium, suggesting that renewal of inflammation within an atheromatous plaque could reactivate latent virus within the lesion and escalate the degree of tissue injury. These in vitro observations are supported by data indicating cyclooxygenase inhibitors may reduce the thrombogenic tendency of atheromatous lesions and may reduce CMV-induced production of ROS as well as CMV replication in smooth muscle cells [32].


   Blocking antigen presentation
Top
 Abstract
 Introduction
 Primary infection/latency
 Apoptosis/mitogenesis
 Blocking antigen presentation
G Protein-coupled receptor...
 Lipid metabolism and CMV
 Conclusions
 References
 
While latency may be the ultimate method by which a virus may survive within the host without exposure of viral antigens to host defenses, it has the distinct disadvantage of preventing spread of the virus to other tissues or transmission to new hosts. CMV, in part, overcomes this by establishing latent infection in most host tissues, but maintaining chronic persistent infection of salivary glands to facilitate transmission to susceptible hosts. If hCMV is reactivated readily from relatively common stresses, there may be frequent opportunities for the host immune system to recognize and destroy the virus. The CMV genome contains several opening reading frames (ORFs) that produce proteins that block or subvert viral antigen expression.

hCMV uses several strategies to inhibit presentation of viral antigens in conjunction with MHC class I and MHC class II complexes. MHC class I proteins are ubiquitously expressed and present antigen to CD8+ T lymphocytes, while MHC II expression is limited to antigen presenting cells, B cells, and monocytes/macrophages, which present antigen to CD4+ T lymphocytes. hCMV encodes several unique short (US) segments that inhibit multiple steps of the antigen presentation pathway [33,34] (Fig. 1Go). US2 causes degradation of the MHC class I complex [34]. US6 inhibits peptide translocation to the endoplasmic reticulum by the MHC-encoded TAP peptide transporter [35]. US3 binds to MHC class I complexes and leads to retention of peptide-loaded complexes within the endoplasmic reticulum (ER) [36]. US11 dislocates class I complexes to the cytosol, where they are rapidly degraded [37]. Taken together, these glycoproteins produce significant reduction of viral antigen presentation at the cell surface with MHC class I complexes. This could potentially lead to an increase in cell killing of CMV-infected cells by natural killer (NK) cells, since these cells are inhibited from activation by the expression of MHC class I antigens on the surface of host cells. hCMV may overcome this problem by production of an MHC class I homolog, a product of the UL18 gene of hCMV, which can bind endogenous peptide, be expressed on cell surfaces, and may protect virus-infected cells against NK cell cytotoxicity by engaging inhibitory receptors on the surface of NK cells [38–40]. Similar sequential disruption of MHC class I processing has been demonstrated for mCMV [33,41,42].



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  		Fig. 1. Human cytomegalo-virus disrupts presentation of viral antigens by the MHC Class I complex. Intracellular viral proteins are normally cleaved by the proteasome, transported into the endoplasmic reticulum (ER) through the TAP transporter, and bind to the MHC I complex for presentation to CD8+ lymphocytes on the cell surface. US6 blocks viral peptide transport through TAP; US3 retains the MHC Class I complex within the ER; and US2 and US11 divert MHC heavy chains to the cytosol where they are degraded. (US = unique short, {alpha} = MHC heavy chains, ß = ß2-microglobulin)

 
CMV also interferes with antigen presentation by MHC class II complexes to CD 4+ lymphocytes. In vitro studies indicate that CMV inhibits MHC class II expression through the Jak/Stat pathway by decreasing levels of Janus kinase 1 [43]. The US2 of hCMV destroys two essential proteins in the MHC class II antigen presentation pathway [44]. MCMV induces early host IL-10 production, which down-regulates MHC class II expression on macrophages [45,46]. In addition, CMV produces its own IL-10 homolog, which may inhibit host production of cytokines including TNF-{alpha}, IFN-{gamma}, IL-2, and granulocyte-monocyte colony stimulating factor [47]. This could lead to a TH1/TH2 switch, since IL-10 is known to be inhibitory to the TH1 pathway. This may be important for virus survival, because protection against CMV, which, like many intra-cellular pathogens, depends more on cell-mediated immune mechanisms. Extracellular viral antigens may be neutralized by specific antibody recognition; however, both hCMV and mCMV produce an Fc receptor that binds IgG [48,49]. Other viruses and some bacteria also produce Fc receptors that may reduce the efficacy of neutralizing antibodies, complement fixation, or interfere with antibody-mediated immune cytotoxicity.


   G Protein-coupled receptor homologs
Top
 Abstract
 Introduction
 Primary infection/latency
 Apoptosis/mitogenesis
 Blocking antigen presentation
 G Protein-coupled receptor...
Lipid metabolism and CMV
 Conclusions
 References
 
Both murine and human CMV contain ORFs that encode G protein-coupled receptor homologs, which bind host chemokines and may sequester chemokines from the extracellular environment [50]. HCMV contains UL33, US27, and US28, which are all transcribed during CMV infection [51]. Unlike wild type virus, US28-deleted virus failed to downregulate either of the chemokines RANTES or MCP-1 in the medium of cultured fibroblasts [50]. Moreover, US28 mediates vascular smooth muscle cell migration in vitro [52], which is an important facet of atherogenesis. An mCMV ORF termed M33 encodes a G protein-coupled receptor with homology to UL33 [53]. An M33-deleted MCMV grows normally in vitro, but shows attenuated growth in vivo. MCP-1 is a C-C chemokine produced in vascular lesions; it causes chemotaxis of monocytes and T lymphocytes, which are major cells found in atheromatous lesions. mCMV infection accelerates inflammation in vascular tissue that overexpress MCP-1 [54]. The present author is investigating whether wild type mCMV is more effective than an M33-depleted strain of mCMV in reducing serum chemokine levels in MCP-1 transgenic mice. If so, it would indicate that M33 may sequester chemokines in vivo and modulate the host inflammatory response.


   Lipid metabolism and CMV
Top
 Abstract
 Introduction
 Primary infection/latency
 Apoptosis/mitogenesis
 Blocking antigen presentation
 G Protein-coupled receptor...
 Lipid metabolism and CMV
Conclusions
 References
 
Hyperlipidemia, especially of low density lipoprotein (LDL), is a risk factor for atherosclerosis. The earliest histologically recognizable lesion of atherogenesis consists of a few lipid laden macrophages (foam cells) beneath the vascular endothelium. Oxidative modification of LDL activates endothelial cells, macrophages, and smooth muscle cells, and has proinflammatory, proatherogenic and prothrombogenic effects. A possible connection between CMV and lipid metabolism was first recognized when Marek’s Disease Virus (MDV), a herpesvirus, was shown to induce atherosclerotic lesions in the aortas of chickens as well as to alter lipid metabolism and lead to accumulation of cholesterol and cholesterol ester within these lesions [55]. hCMV also increases levels of neutral lipids in cultured human saphenous vein smooth muscle cells [56]. In CMV-infected monocytes, the presence of oxidized LDL and endothelial cells within the culture medium increased MIEP activity over seven-fold [57]. hCMV infection of human aortic smooth muscle cells in vitro stimulated the expression of scavenger receptor mRNA and the uptake of oxidized and acetylated LDL [18]. We reported that CMV-seropositvity is associated with higher serum cholesterol levels in young females, although the clinical significance of this finding is unclear [58].


   Conclusions
Top
 Abstract
 Introduction
 Primary infection/latency
 Apoptosis/mitogenesis
 Blocking antigen presentation
 G Protein-coupled receptor...
 Lipid metabolism and CMV
 Conclusions
References
 
Cytomegalovirus infection has been linked to atherosclerosis through epidemiologic studies, the finding of viral DNA within atheromatous lesions, and studies demonstrating increased development of atherosclerosis in animal models [13,59]. Together, these studies provide strong circumstantial evidence that CMV may be a risk factor for atherosclerosis. However, a causal relationship has not been proven and it is possible that the microenvironment of atheromatous lesions is simply more suitable to CMV survival. Even if CMV does not initiate vascular lesions, it may be an important contributing factor to atherogenesis by accelerating or exacerbating existing lesions. hCMV infection has been shown to produce in vitro many of the inflammatory responses that are hallmarks of atherosclerosis (Fig. 2Go). These responses are common to many chronic inflammatory conditions, and are not unique to either CMV infection or atherosclerosis. Although CMV antigens and DNA can be found in atheromatous plaques, other organisms, such as Chlamydia pneumoniae, may also be present [60]. However, these infections may be largely latent with little or no inflammatory response attributable to the presence of the microorganism.



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  		Fig. 2. An atheromatous lesion depicting multiple cells, cytokines, chemokines, growth factors, lipids, and components of free radical formation that are common to atherosclerosis and CMV infection. (CMV = cytomegalovirus, ROS = reactive oxygen species, ox-LDL = oxidized low density lipo-protein, VCAM = vascular cell adhesion molecule, ICAM = intercellular adhesion molecule, MCP-1 = monocyte chemoattractant protein-1, M-CSF = monocyte-colony stimulating factor, PDGF = platelet derived growth factor, M{Phi} = monocytes/macrophages [purple], SMC = smooth muscle cells [red], vascular endothelium [brown]).

 
There is broad agreement that atherosclerosis is a chronic inflammatory response of the vascular wall to injury and may progress through multiple periods of acute inflammation followed by relative quiescence [2]. Several important factors may allow CMV infection to contribute to formation of the atherogenic lesion: (a) reactivation from latency appears to be a common event giving the virus ample opportunity to contribute to atherogenesis; (b) CMV is often present in atheromatous plaques and virus replication is induced by several factors activated during inflammatory episodes known to occur during atherogenesis, again amplifying the opportunity for CMV to contribute to the inflammatory damage; (c) CMV may be capable of contributing to the lipid perturbations seen within affected vascular walls, and in particular may increase the oxidation of LDL and affect cholesterol accumulation (or conversely, CMV may simply thrive in the particular lipid microenvironment found in atheromatous lesions); (d) once activated, the IE genes of CMV in turn activate many pro-inflammatory host genes creating the probability of a cyclic succession of inflammatory damage to vascular walls, no matter what the initiating factor may be; and (e) CMV dampens the inflammatory assault by immunoevasive techniques that allow the virus to survive in inflamed tissues until reactivated by factors directly involving the arterial wall, or more distant factors that may elicit virus reactivation.

CMV infection or reactivation elicits and then dampens the inflammatory response. For example, IFN-{gamma} and TNF-{alpha} are both upregulated in monocytes following infection. However, viral infection also induces differentiation of monocytes into hCMV-permissive macrophages, which are resistant to the antiviral effects of these cytokines [61], thus protecting viruses from the detrimental action of these cytokines. Despite recurrent or persistent inflammation of the artery wall, CMV may be able to survive within these vascular lesions and persist through multiple episodes of reactivation and viral replication. In this manner CMV may contribute to the chronic fibro-inflammatory progression of atheroma formation and vessel stenosis. Finding reactivated hCMV within early active atheromatous lesions in young patients would support the concept that CMV could contribute to atherogenesis during lesion development. It would also be useful to demonstrate virus reactivation in humans or animal models in concert with exacerbations by other known risk factors, such as periods of hypertension or hyperlipidemia.

It is likely that CMV infection or reactivation is simply one of many environmental factors that may contribute to atherogenesis. However, it may be possible to control or prevent that contribution by controlling or eliminating the infection. If that is the case, clinical improvement and prevention of the sequelae of atherosclerosis should be possible with adequate antiviral therapy.


   References
Top
 Abstract
 Introduction
 Primary infection/latency
 Apoptosis/mitogenesis
 Blocking antigen presentation
 G Protein-coupled receptor...
 Lipid metabolism and CMV
 Conclusions
 References
 

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