Open access

The Footprint of CMV Infection May Last a Lifetime

Written By

Patricia Price

Submitted: June 28th, 2012 Published: May 29th, 2013

DOI: 10.5772/54798

Chapter metrics overview

1,940 Chapter Downloads

View Full Metrics

1. Introduction

Cytomegalovirus (CMV) is a β-herpesvirus able to replicate in fibroblasts, endothelial cells and monocytes [1]. CMV infection is usually asymptomatic, but causes a mononucleosis-like illness in some individuals. CMV disease can manifest as a syndrome or as an acute infection of an organ or tissue. CMV syndrome is characterized by fever, leukopenia, hepato-splenomegaly, myalgias and occasionally pneumonitis. Sites of acute CMV infection include brain, heart, kidneys, liver and eyes. CMV colitis and CMV enteritis are manifestations of CMV disease in solid organ transplant recipients, bone marrow transplant recipients and HIV patients [2]. CMV retinitis was a common AIDS-defining illness before antiretroviral therapy (ART) became available, and remains a significant cause of blindness in HIV patients in the developing world [3]

In considering the role of CMV in human health, many studies have overlooked the fact that 50-90% of all populations are seropositive. As the virus has the capacity of latency and is known to be reactivated by “stress” (immunosuppression), it is likely that most people harbour latent virus [2]. Much of literature related to CMV is derived from studies of laboratory mice infected with a related virus Murine Cytomegalovirus (MCMV), which shares a similar genomic organisation and some sequence homology with human CMV. It is promoted as a useful model to study host-interaction because it shares similar in-vivo properties to human CMV after infection. Differences in the susceptibility of inbred strains of laboratory mice to MCMV infection has allowed several mechanisms of virological control to be characterised [4, 5], but there are several areas where extrapolation to human CMV is problematic.

  1. CMV has over 200 reading frames with potential to encode proteins [1].Of the proteins characterised, many are redundant for viral replication in vitro. These include homologues of host genes “picked up” since mice and humans diverged during mammalian evolution. If we assume that such genes are retained because they confer a survival advantage, then the pathogenic pathways initiated by the murine and human viruses must be subtly different. This has been demonstrated with CMV-encoded chemokines [6].

  2. Susceptibility to murine CMV is MHC (murine H-2) dependent. This is evident in cultured cells and immunodeficient hosts so it is not related to CD8+ T-cell responses. Rather some H-2 Class I proteins appear to act as a cell surface receptor. There is no evidence that human HLA proteins have this role [7].

  3. Without external immunosuppression, adult laboratory mice of susceptible strains can readily be infected with murine CMV at a dose that destroys their spleen and other organs, and may cause death [4].This is not seen in people, but has been used in many studies to examine immune responses to CMV.

  4. In vitro infection of monocytes, macrophages and dendritic cells with murine CMV [8, 9] creates cells which remain intact but selectively loose secondary functions. This is interesting but not an important mode of immunoregulation, as only a small percentage of cells of these lineages are infected in patients or more resistant mice.

To avoid translational issues between studies of MCMV in mice and HCMV in humans, we need to look more closely at people infected with CMV. This must include primary disease and the effects of long term asymptomatic CMV infection in immune competent hosts. A lesson that we can take from MCMV is the effects on multiple cells and organs, including the adrenals, pancreas and salivary glands [4, 5, 10, 11]. Sensitive PCR-based viral load assays are now available, but these are only routinely applied to blood, urine or saliva of patients at risk of acute disease. There is little probability of detecting latent CMV. Here we present a tool to evaluate the lifetime effects of CMV on human health - the footprint of CMV. We also summarise evidence that natural killer (NK) cells may regulate the footprint of CMV. The likely impact in HIV patients is presented as Figure 1.

Figure 1.

HIV disease has several avenues to enhance the footprint of CMV and thereby promote cardiovascular disease.


2. Immune control of CMV

T-cell and antibody responses may reflect CMV replication rather than protect against it. CD8+ T-cell responses to CMV can be assessed by IFNγ ELISpot or using tetramers or pentamers that mark cells reacting with a particular CMV peptide presented by a particular HLA molecule (usually HLA-A2). Gamadia et al [12]reported that frequencies of CMV-specific CD8+ T-cells were significantly higher in immunosuppressed transplant recipients than in healthy donors, suggesting that these responses may reflect exposure rather than protection. This is consistent with evidence that CMV encodes proteins that down regulate T-cell recognition of infected cells, and thus evade immune detection. This includes the degradation of HLA class I and II molecules by unique short (US) proteins and disruption of antigen processing by an infected antigen-presenting cell [13].CMV-specific cells predominantly have an effector-memory or senescent phenotype (CD45R0+CD27CCR7 or CD45RA+CD27CCR7, resp.). Subsequent studies suggest that a rapid CD4+ T-cell response was also essential to avoid symptomatic primary CMV infection in renal transplant recipients [14], but the cells critical for the maintenance of latency have not been identified.

Extensive studies of MCMV infection in laboratory mice have mapped protective NK cell-mediated responses to the Ly49 gene cluster [equivalent to human Killer Cell Immunoglobulin-like receptor (KIR) genes]. Mouse strains have distinct Ly49 gene repertoires, which correlate with resistance to MCMV [15]. The activating receptor Ly49H is implicated in protection, and several members of the Ly49 family interact with MCMV encoded proteins [16]. In mice without a protective NK response (eg: through Ly49H), MCMV infections are eventually controlled by T-cells. CD4+ T-cells are needed to control MCMV persistence in the salivary gland [17]. CD8+ T-cells recognising immediate early (IE) epitopes are also implicated in control of reactivated MCMV, where frequent boosting expands specific CD8+ T-cell clones. MCMV encodes genes able to regulate MHC class I expression, demonstrating an evolutionary impetus to avoid CD8+ T-cell responses. Critical epitopes and H-2 loci initiating protective CD8+ T-cell responses have been identified, but it is a limitation that all studies use laboratory strains of MCMV rather than primary isolates [18]. This highlights the need to study human CMV disease.

Direct evidence that NK cells can control CMV in humans is available from a study of a congenitally T-cell deficient child with acute CMV infection and a 10-fold expansion of NK cells with restricted receptor diversity. Acute illness resolved and NK cells returned to normal levels with clearance of plasma CMV DNA [19].This fits teleological and genetic evidence that NK cells control CMV. Human and mouse CMV diverged with their host species and have independently evolved proteins able to subvert protective NK responses [20]. This includes homologues of HLA-G (UL18) and HLA-E signal peptide (UL40), which interact with NK inhibitory receptors (LIR-1 and NKG2C, resp.) (Reviewed in[21] ) In support of a role for NK cells in CMV and HIV disease, we showed that heterozygous carriage of allele 2 at LIR-1 (rs1061680; LILRB1 I142T) associated with CMV disease and nadir CD4+ T-cell counts [22].

A role for NK cells in the control of CMV is also consistent with evidence that carriage of more genes for activating KIR receptors protects against CMV reactivation in immunosuppressed renal [23, 24] and bone marrow [25, 26] transplant patients. KIR receptors in man comprise both inhibitory and activating members (as do Ly49 genes in mice). The ligands for most inhibitory KIR are allelic epitopes of the classical class I HLA proteins (reviewed in[27]). In contrast, ligands for most of the activating KIR are unknown. An exception is KIR2DS1, which interacts with HLA-C2. [28, 29]. Several groups have attempted to identify the CMV-protective KIR gene, but this is complicated by linkage disequilibrium in the KIR gene complex. Inhibition of NK killing of fibroblasts infected by CMV has been demonstrated by several groups [30].This study implicated UL18 but this may depend on the NK donor’s genotype. Although the roles of specific NK receptors in CMV disease are unclear, increased expression of LIR-1 [31, 32] and/or NKG2C [33, 34] is a consequence (footprint) of CMV replication. This has potential as a tool to assess a history of CMV reactivation.


3. CMV has a footprint in healthy aging and cardiovascular disease

Associations between CMV and vasculopathy have been described since 1987 [35] and attributed to immunopathological events initiated by viral replication. Our studies of MCMV in inbred mice showed that susceptible BALB/c mice develop myocarditis in which CD8+ T-cells accumulate in the myocardium and persist for 12 months despite clearance of viral antigen by day 3 [36]. In C57BL/6 mice have a protective NK response [5] and display only mild resolving myocarditis. To evaluate the evidence available in patients requires consideration of the underlying mechanisms.

Inflammation and activation of immune cells features throughout atherogenic plaque formation, which is the principle condition of cardiovascular disease (CVD). Pathogenesis of atherosclerotic plaques on vessel walls begins with acute inflammation resulting in endothelium dysfunction [37]. Many life-style risk factors can reduce the integrity of endothelium. The accumulation of low density lipoproteins (LDL) in intimal space by diffusion and its oxidation can cause endothelial cell injury and inflammation [38]. Secretion of vascular cell adhesion molecule-1 (VCAM-1) and up-regulation of selectins and integrins facilitates leukocyte adhesion to vessel walls. Inflammatory cytokines such as IL-1 and TNF-α induce expression of chemokines (eg: CCL2, CXCL8, CX3CL1) by endothelial cells, recruiting T-cells and monocytes and facilitating their transmigration into the intimal space. Monocytes internalize LDL and differentiate into macrophages which promote inflammation and leukocyte migration into developing plaques by secretion of CX3CL1/CX3CR1, interferon-γ (IFNγ) and CCL2 [39, 40] and generation of reactive oxygen species [41]. Hyperlipidemia, macrophage death and consequential irregular surfaces of vessel endothelium promote growth of the atherosclerotic lesion. Smooth muscle cells migrate from the media to intimal space aided by lytic enzymes. This contributes to plaque instability [39]. Smooth muscle cells proliferate in intimal space and also adhere to monocytes [42], thickening arterial walls and occluding the vessel. Rupture of the plaque can result in infarction. Myocardial infarcts (MI) refer to rupture of plaque in the coronary artery. The carotid artery is also a frequent site of plaque formation and thickness of the intima at this site can indicate clinical and sub-clinical CVD [43].

Active CMV infection has been associated with the onset of autoimmune disorders in transplant patients and healthy donors. The development of autoimmune antibodies following reactivation of CMV in transplant patients has been linked to graft versus host disease and graft rejection. Hypergammaglobulinemia and autoantibody production can also be a feature of CMV-induced mononucleosis. There have been several case reports of healthy individuals developing acute CMV infection preceding vasculitis or encephalitis. In a case of encephalitis, treatment of active CMV with valganciclovir resolved symptoms, but CMV-specific CD4+ and CD8+ T-cells remained 10 months after disease onset [44-]. The development of autoimmune vasculitis, systemic lupus erythematosus, sclerodoma and necrotizing vasculitis have been associated with CMV replication [46]. Anti-phospholipid antibodies have been shown to activate endothelial cells and CMV transcription [47], suggesting a feedback amplification loop.

CMV seropositivity has been correlated with a greater risk of all-cause mortality in the elderly [48-]. Although it is rare for CMV to be identified as the primary cause of death, CMV prevalence in the older population can be as high as 100% [52]. An in-depth study following Latinos aged 60-101 years for a period of 9 years (n=1,468) showed that those with high CMV antibody titres were 1.43 times more likely to die and had 1.35 times greater risk of CVD-associated mortality than those with low CMV antibody titres [51]. 96% of the participants were CMV seropositive. Factors significantly (p<0.05) associated with mortality included age, female gender, low education level and levels of inflammatory markers (TNF, IL-6, C-reactive protein). Elderly CMV-seropositive patients respond less well to seasonal influenza vaccination than those with low or negative CMV seropositivity [50, 53]. This suggests dysfunction of the immune system and could account for the increased risk of all-cause mortality.

In older CMV-seropositive adults, up to 23% of the T-cell population can be CMV-specific. For example, NLV peptide-specific CD8+ T-cells alone comprised a median 3% (range = 0.4-5.6%) of CD8+ T-cells in donors aged 90 [89-96] years. CMV-specific T-cells are generally CD28-negative(an immunosenescent phenotype also associated with expression of CD57 and shortened telomeres) and have limited proliferative potential, but may produce IFNγ. Their accumulation correlates with immunologic aging or ‘‘immunosenescence’’ evident in the entire T-cell population assayed ex vivo [54-].The accumulation of senescent CMV-reactive T-cells was greatest in frail and institutionalized elderly donors [58].Repeated sub-clinical CMV infections may expand CMV-specific T-cells clones until they suppress homeostatic expansion of other T-cells. Alternatively the expanded clones of CMV-reactive cells may bias the population and dilute cells of other specificities - explaining why EBV-reactive T-cells do not show a senescent phenotype [54].

However chronic CMV reactivation may have wider consequences than just an aging immune system. CMV infects endothelial cells in acute stages of infection and it is proposed they could also be a site of latent infection [59, 60]. Studies of murine CMV in mice have identified endothelial cells as a site of viral latency [61], whilst several studies demonstrated human CMV in arterial walls of atherosclerotic and non-atherosclerotic patients [62, 63]. A study of tissues removed during surgery for abdominal aortic aneurysm associated the presence of CMV DNA in smooth muscle cells with expression of inflammatory mediators and implicated CMV in the pathology [64]. Accordingly higher CMV antibody titres are associated with increased diastolic and systolic blood pressure in young men [65] and CMV seropositivity is more frequent in coronary artery disease requiring surgery[66]. Increased expression of LIR-1 on NK cells (a footprint of CMV) is also associated with atherosclerosis [67].Stronger T-cell responses to CMV also associate with severe cardiovascular changes seen in HIV patients [68].

The chemokine, fractalkine (CX3CL1) and its receptor CX3CR1 are membrane-bound proteins. CX3CL1 can be cleaved from a cell surface through TNFα signal pathways to mediate attraction and then firm adhesion of lymphocytes expressing CX3CR1 to endothelium. T-lymphocytes and monocytes express CX3CR1, whilst monocytes, endothelial cells and smooth muscle cells can be induced to express CX3CL1 by TNFα, IFNγ, IL-1 and LPS [37, 69, 70].CX3CR1 is found in atherosclerotic plaques and its role in plaque formation and mediation by inflammation is of interest in the management of CVD [69]. An in vitro system co-coculturing CMV infected endothelial cells and peripheral blood mononuclear cells established the principle that CMV specific CD4+ T-cells can induce CX3CL1 production in CMV infected endothelial cells. CX3CL1 aids the ingress of monocytes and NK cells which are capable of killing the CMV infected endothelial cell [71].

Monocytes in atherosclerotic plaques express higher levels of CX3CR1 and CX3CL1 promoting chemotaxis of monocytes and T-lymphocytes to the plaque [72].CX3CL1 can be expressed by epithelial cells, but vascular endothelial cells and smooth muscle cells do not normally express CX3CL1. TNFα can induce expression of CX3CR1/L1 in these tissues [70], which corresponds with detection of CX3CR1/L1 at a later stage of plaque formation. Sacre et al. reported that CD4+CX3CR1+T-cells produced more TNFα and IFN γ in vitro than CD4+CX3CR1- T-cells. This is consistent with a potential feedback mechanism in which CD4+CX3CR1+ T-cells exacerbate plaque formation. Immuno-histochemical staining of coronary arterial wall samples from HIV patients with atherosclerosis showed a presence of CX3CR1, CD4 and CD3 at early stages of atherogenesis, so CD4+CX3CR1+ T-cells could initiate plaque formation [73].


4. HIV patients stable on ART have a stronger footprint of CMV

In HIV patients with suppressed HIV replication on ART, the recovery of CD4+ T-cell counts is limited by replenishment from the thymus and the loss of T-cells through persistent chronic immune activation [74, 75].Persistent CD4+ T-cell deficiency is most common in patients with low nadir CD4+ T-cell counts (<100 cells/µl) even though some patients beginning ART with severe T-cell depletion achieve effective immune reconstitution [76]. Patients with abundant thymic tissue show a faster and higher return of naïve CD4+ T-cells after ART. However the thymus is a site of HIV replication. Infected thymocytes may die (through necrosis or apoptosis) or survive and carry the HIV provirus to their progenies (establishing latent infection). As HIV disease progresses, the thymus becomes prematurely atrophic, with changes similar to those seen in old age. For example, the thymus of a 30 year-old with late stage AIDS may be morphologically similar to the normal atrophic thymus of a 60 year-old [77].

Thymic dysfunction and the consequent release of autoreactive T-cells into circulation are implicated in the autoimmune and immunopathological conditions normally seen in old age - conditions that are more common in HIV patients (including those with a virological response to ART) than in the general population. This includes cardiovascular disease – which is influenced by the ART regime, life-style factors (smoking, exercise etc.) and other infections, notably CMV. CMV infection is more prominent in HIV patients, so its role in immunological aging and cardiovascular disease requires evaluation [78].

Over 50% of healthy individuals and 90% of individuals living with HIV are seropositive for CMV. Retinitis is the most common manifestation of CMV disease in HIV-infected individuals, affecting up to 40% of American AIDS patients, and many HIV patients in the developing world [3, 79].Treatment of systemic CMV disease is expensive and protracted, so prophylaxis is suspended once patients are stable on ART. As discussed earlier, CMV has the capacity for latency with frequent reactivation triggered by inflammatory mediators, including TNF [80]. Immune activation in treated and untreated HIV disease increases levels of this cytokine in circulation and tissues [81], so frequent subclinical reactivation of CMV is expected.

It appears likely that CMV and thymic insufficiency are synergistic in their effects on T-cell profiles in HIV patients. This is supported by evidence that homeostatic expansion of existing T-cells maintains T-cell numbers in the absence of thymic output, so age-related declines in immune function are accentuated in patients thymectomised in early childhood. This was clearest in individuals with strong T-cell responses to CMV IE and pp65 antigens [82].Accumulation of CMV –specific T-cells with an immunosenescent phenotype is greater in HIV patients than in age-matched controls [83, 84]. The importance of CMV in immune activation and immunosenesence in HIV patients is confirmed by evidence that immune activation was reduced when patients were treated with valgancyclovir [85].

Our studies of HIV patients also suggest that elevated T-cell and humoral responses to CMV reflect frequent reactivation. We investigated HIV patients who began antiretroviral therapy (ART) with extreme immunodeficiency and maintained a virological response until they were >50 years old. One can assume that they had a high burden of CMV pre-ART as many had experienced CMV retinitis. These HIV patients retained high titres of antibody reactive with CMV after 14 [13-16] years on ART and displayed elevated IFNγ responses to an immediate early peptide of CMV(unpublished data).Such patients display accelerated cardiovascular disease that correlates with responses to CMV [86].

CD4+CX3CR1+ T-cells may help explain the role of CMV-specific cells in development of atherosclerosis in HIV patients, but the mechanisms requires further investigation. Interest in CX3CR/L in atherosclerosis is focussed by three findings reported in several studies.

  1. Atherosclerosis is an inflammatory disease that is more frequent in HIV patients and cannot be attributed to ART cardiotoxicity alone [87, 88, 89, 90, 91].

  2. HIV patients have a high proportion of CMV-specific T-cells [82, 83, 92]

  3. CX3CR1 is found in atherosclerotic lesions and is expressed by T-cells [69,70]

A study of CX3CR1+ CD4+ T-cells and their implications in CVD was conducted in HIV-infected (n=29) and uninfected (n=48) individuals. The frequency of CD4+CX3CR1+ T-cells correlated with increasing carotid intima-media thickness (cIMT) in HIV-infected individuals. These cells were antigen primed (CD45RA-, CD27-), activated (HLA-DR+) and immunosenescent (CD57+) [73].

It may also be important that NK function is deficient in HIV patients. HIV infection changes the proportions of NK cell subsets, and expression of their activating and inhibitory receptors. It also perturbs their cytotoxic functions and cytokine production [93].Our group has published two studies of previously immunodeficient Australian patients, stabilised for many years on ART:

  1. CD4+ T-cell IFNγ responses to CMV were inversely related to CD4+ T-cell counts before ART in patients who began ART with <60 CD4+ T-cells/μL, but IFNγ responses of NK cells to an unrestricted target (K562 cells) were directly proportional to nadir CD4+ T-cell counts [94].This establishes that NK cells don’t follow the same trends as CD4+ T-cells on ART and do keep the imprint of the pre-ART immune system for many years.

  2. NK cell IFNγ responses and proportions of CD56loCD16+ NK cells were positively correlated and lower in patients than controls (confirming persistent NK dysfunction). Proportions of CD56hiCD16neg NK cells (a phenotype associated with cytokine production) correlated inversely with CD4+ T-cell counts after ART and expression of perforin in this NK subset was higher in HIV patients than healthy controls. So these NK cells may compensate for T-cell deficiency [95].


5. CMV remains an important pathogen after renal transplantation

CMV reactivation (in previously seropositive recipients) or primary infection (in any recipient) is the most common infectious complication in renal transplantation [96].In the 1970’s one in three recipients experienced pathologies associated with CMV. In one study of 141 patients, 12 died with disseminated CMV infection [97, 98].

In Australia, prophylaxis (valganciclovir) is routinely administered for 12-26 weeks after transplantation, according to a formula that considers donor and recipient CMV seropositivity and clinical risk. Under an equivalent regime, CMV recurred in 14/43 (33%) seropositive patients and in 4/19 (21%) patients after primary infection [99]. CMV remains a significant cause of graft loss despite prophylaxis and in the longer term, CMV reactivations are implicated in deterioration in renal function [100, 101], exhaustion or senescence of T-cells and cardiovascular disease.

Cardiovascular disease is recognised as a long term complication of renal transplantation, but a recent review [102] attributed this to immunosuppression. CMV antigenaemia (pp65) in the first year post-transplant did not predict cardiovascular disease over the next 2 years [102], but the study did no assess the longer term footprint of CMV disease. It is notable that Gomez et al [103] associated cardiovascular disease with CMV seropositivity over 1 year post-transplant in patients given oral ganciclovir.


6. Conclusions

The immune response to CMV has been studied extensively in mice and evidence is now accumulating from studies in humans. It is clear that NK cell and T cell responses are both important and that they influence each other. We propose a “footprint of CMV” as a tool to investigate the short and long term effects of CMV infection.

The footprint may include

  1. CMV DNA detected by a sensitive PCR assay of blood, saliva or urine.

  2. CMV-peptide/HLA tetramer positive CD8 T cells: The number of these cells in the blood is thought to reflect an accumulation of cells responding to CMV replication.

  3. IFN-γ responses of CD4+ and CD8+ T-cells to CMV antigens enumerated by ELISPOT or flow cytometry.

  4. Anti-CMV antibody detected by ELISA

  5. Expression of NKG2C and LIR-1 on NK cells and T cells: NKG2C is expressed on a very small proportion of NK cells in CMV-seronegative subjects but expressed on a substantial proportion of NK cells from CMV seropositive subjects [31,32,33]and is considered a hallmark of CMV exposure. This probably reflects expansion of a small NK cell population in response to CMV infection. LIR-1 expression is also increased in subjects with higher titres of CMV antibody.

The resulting holistic view of the immune response in man will be a foundation for future studies aimed at identifying phenotypes associated with protection and those individuals who will benefit most from CMV prophylaxis.


  1. 1. Murphy E, Yu D, Grimwood J, Schmutz J, Dickson M, Jarvis MA, Hahn G, Nelson JA, Myers RM, Shenk TE. Coding potential of laboratory and clinical strains of human cytomegalovirus. Proc Natl Acad Sci USA, 2003; 100 14976-81.
  2. 2. Landolfo S, Gariglio M, Gribaudo G, Lembo D. The human cytomegalovirus. Pharmacol Therap 2003; 269-297
  3. 3. Ganekal S, Jhanji V, Dorairaj S, Nagarajappa A. Evaluation of Ocular Manifestations and Blindness in HIV/AIDS Patients in a Tertiary Care Hospital in South India. Ocul Immunol Inflamm. 2012; 1-6
  4. 4. Price P, Olver SD. Animal Models for Human Immunopathological diseases: Cytomegalovirus Disease. ClinImmunolImmunopath 1996; 80:215-24.
  5. 5. Scalzo AA, Yokoyama WM. Cmv1 and natural killer cell responses to murine cytomegalovirusinfection.Curr Top Microbiol Immunol 2008; 321:101-22
  6. 6. Farrell HE, Abraham AM, Cardin RD, Sparre-Ulrich AH, Rosenkilde MM, Spiess K, Jensen TH, Kledal TN, Davis-Poynter N. Partial functional complementation between human and mouse cytomegalovirus chemokine receptor homologues. J Virol. 2011; 85(12): 6091-6095
  7. 7. Price P. Are MHC proteins cellular receptors for CMV? Immunol Today. 1994; 15(6):295-6.
  8. 8. Van Bruggen I, Price P, Robertson TA, Papadimitriou JM. Morphological and functional changes during cytomegalovirus replication in murine macrophages. J Leukoc Biol. 1989; 46:508-20.
  9. 9. Andrews DM, Andoniou CE, Granucci F, Ricciardi-Castagnoli P, Degli-Esposti MA. Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. Nat Immunol. 2001; 2(11):1077-84.
  10. 10. Price P, Baxter AG, Allcock RN, Papadimitriou JM. Factors influencing the effects of murine cytomegalovirus on the pancreas. Eur J Clin Invest. 1998 ;28:546-53.
  11. 11. Price P, Olver SD, Silich M, Nador TZ, Yerkovich S, Wilson SG. Adrenalitis and the adrenocortical response of resistant and susceptible mice to acute murine cytomegalovirus infection. Eur J Clin Invest. 1996;26:811-19
  12. 12. Gamadia LE, Rentenaar RJ, Baars PA, Remmerswaal EBM, Surachno S, Weel JF, Toebes M, Differentiation of cytomegalovirus-specific CD8+ T cells in healthy and immunosuppressed virus carriers. Blood. 2001;98(3):754-61.
  13. 13. Lin A, Xu H, Yan W. Modulation of HLA expression in human cytomegalovirus immune evasion. Cell Mol Immunol. 2007;4(2):91-8.
  14. 14. Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood. 2003;101(7):2686-92
  15. 15. Sumaria N, van Dommelen SL, Andoniou CE, Smyth MJ, Scalzo AA, Degli-Esposti MA. The roles of interferon-gamma and perforin in antiviral immunity in mice that differ in genetically determined NK-cell-mediated antiviral activity. Immunol Cell Biol. 2009; 87(7):559-66.
  16. 16. Pyzik M, Gendron-Pontbriand EM, Vidal SM. The impact of Ly49-NK cell-dependent recognition of MCMV infection on innate and adaptive immune responses. J Biomed Biotechnol. 2011;2011:641702.
  17. 17. Arens R, Loewendorf A, Her MJ, Schneider-Ohrum K, Shellam GR, Janssen E, Ware CF, Schoenberger SP, Benedict CA. B7-mediated costimulation of CD4 T cells constrains cytomegalovirus persistence. J Virol. 2011;85(1):390-6.
  18. 18. Lemmermann NA, Böhm V, Holtappels R, Reddehase MJ. In vivo impact of cytomegalovirus evasion of CD8 T-cell immunity: facts and thoughts based on murine models. Virus Res. 2011;157(2):161-74.
  19. 19. Kuijpers TW, Baars PA, Dantin C, van den Burg M, van Lier RA, Roosnek E. Human NK cells can control CMV infection in the absence of T cells. Blood. 2008 Aug 1;112(3):914-5.
  20. 20. Revilleza MJ, Wang R, Mans J, Hong M, Natarajan K, Margulies DH. How the virus outsmarts the host: function and structure of cytomegalovirus MHC-I-like molecules in the evasion of natural killer cell surveillance. J Biomed Biotechnol. 2011;2011:724607
  21. 21. Wilkinson GW, Tomasec P, Stanton RJ, Armstrong M, Prod'homme V, Aicheler R, McSharry BP, Rickards CR, Cochrane D, Llewellyn-Lacey S, Wang EC, Griffin CA, Davison AJ. Modulation of natural killer cells by human cytomegalovirus. J Clin Virol. 2008 Mar;41(3):206-12.
  22. 22. Affandi JS, Aghafar ZK, Rodriguez B, Lederman MM, Burrows S, Senitzer D, Price P. Can immune-related genotypes illuminate the immunopathogenesis of cytomegalovirus disease in human immunodeficiency virus-infected patients? Hum Immunol. 2012 Feb; 73(2):168-74.
  23. 23. Stern M, Elsässer H, Hönger G, Steiger J, Schaub S, Hess C. The number of activating KIR genes inversely correlates with the rate of CMV infection/reactivation in kidney transplant recipients. Am J Transplant. 2008 Jun;8(6):1312-7.
  24. 24. Zaia JA, Sun JY, Gallez-Hawkins GM, Thao L, Oki A, Lacey SF, Dagis A, Palmer J, Diamond DJ, Forman SJ, Senitzer D. The effect of single and combined activating killer immunoglobulin-like receptor genotypes on cytomegalovirus infection and immunity after hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009 Mar;15(3):315-25.
  25. 25. Cook M, Briggs D, Craddock C, Mahendra P, Milligan D, Fegan C, Darbyshire P, Lawson S, Boxall E, Moss P. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood. 2006 Feb 1;107(3):1230-2.
  26. 26. Chen C, Busson M, Rocha V, Appert ML, Lepage V, Dulphy N, Haas P, Socié G, Toubert A, Charron D, Loiseau P. Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders. Bone Marrow Transplant. 2006 Sep;38(6):437-44.
  27. 27. Jamil KM, Khakoo SI. KIR/HLA interactions and pathogen immunity. J Biomed Biotechnol. 2011; 298348.
  28. 28. Foley B, De Santis D, Lathbury L, Christiansen F, Witt C. KIR2DS1-mediated activation overrides NKG2A-mediated inhibition in HLA-C C2-negative individuals. Int Immunol. 2008 Apr;20(4):555-63.
  29. 29. Chewning JH, Gudme CN, Hsu KC, Selvakumar A, Dupont B. KIR2DS1-positive NK cells mediate alloresponse against the C2 HLA-KIR ligand group in vitro. J Immunol. 2007 Jul 15;179(2):854-68.
  30. 30. Prod'homme V, Griffin C, Aicheler RJ, Wang EC, McSharry BP, Rickards CR, Stanton RJ, Borysiewicz LK, López-Botet M, Wilkinson GW, Tomasec P. The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+ but activates LIR-1- NK cells. J Immunol. 2007 Apr 1;178(7):4473-81.
  31. 31. Wagner CS, Riise GC, Bergström T, Kärre K, Carbone E, Berg L. Increased expression of leukocyte Ig-like receptor-1 and activating role of UL18 in the response to cytomegalovirus infection. J Immunol. 2007 Mar 15;178(6):3536-43.
  32. 32. Berg L, Riise GC, Cosman D, Bergström T, Olofsson S, Kärre K, Carbone E. LIR-1 expression on lymphocytes, and cytomegalovirus disease in lung-transplant recipients. Lancet. 2003 Mar 29;361(9363):1099-101.
  33. 33. Gumá M, Budt M, Sáez A, Brckalo T, Hengel H, Angulo A, López-Botet M. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood. 2006 May 1;107(9):3624-31.
  34. 34. Hadaya K, de Rham C, Bandelier C, Bandelier C, Ferrari-Lacraz S, Jendly S, Berney T, Buhler L, Kaiser L, Seebach JD, Tiercy JM, Martin PY, Villard J.Natural killer cell receptor repertoire and their ligands, and the risk of CMV infection after kidney transplantation. Am J Transplant. 2008 Dec;8(12):2674-83.
  35. 35. Adam E, Melnick JL, Probtsfield JL, Petrie BL, Burek J, Bailey KR, McCollum CH, DeBakey ME. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet. 1987 Aug 8; 2(8554):291-3.
  36. 36. Price P, Eddy KS, Papadimitriou JM, Faulkner DL, Shellam GR. Genetic determination of cytomegalovirus-induced and age-related cardiopathy in inbred mice. Characterization of infiltrating cells. Am J Pathol. 1991 Jan; 138(1):59-67.
  37. 37. Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14; 340(2):115-26.
  38. 38. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012 Sep; 32(9):2045-51.
  39. 39. Liu H, Jiang D. Fractalkine/CX3CR1 and atherosclerosis. Clin Chim Acta. 2011 Jun 11;412(13-14):1180-6.
  40. 40. Kraemer, R. Regulation of Cell Migration in Atherosclerosis Current Atherosclerosis Reports 2000 2(5):445–452
  41. 41. Schindhelm RK, van der Zwan LP, Teerlink T, Scheffer PG. Myeloperoxidase: a useful biomarker for cardiovascular disease risk stratification? Clin Chem. 2009 Aug;55(8):1462-70.
  42. 42. Meng L, Park J, Cai Q, Lanting L, Reddy MA, Natarajan R. Diabetic conditions promote binding of monocytes to vascular smooth muscle cells and their subsequent differentiation. Am J Physiol Heart Circ Physiol. 2010 Mar; 298(3):H736-45.
  43. 43. Maggi P, Perilli F, Lillo A, Carito V, Epifani G, Bellacosa C, Pastore G, Regina G. An ultrasound-based comparative study on carotid plaques in HIV-positive patients vs. atherosclerotic and arteritis patients: atherosclerotic or inflammatory lesions? Coron Artery Dis. 2007 Feb;18(1):23-9.
  44. 44. Toyoda M, Galfayan K, Galera OA, Petrosian A, Czer LS, Jordan SC. Cytomegalovirus infection induces anti-endothelial cell antibodies in cardiac and renal allograft recipients. Transpl Immunol. 1997 Jun;5(2):104-11
  45. 45. Varani S, Muratori L, De Ruvo N, Vivarelli M, Lazzarotto T, Gabrielli L, Bianchi FB, Bellusci R, Landini MP. Autoantibody appearance in cytomegalovirus-infected liver transplant recipients: correlation with antigenemia. J Med Virol. 2002 Jan; 66(1):56-62.
  46. 46. Varani S, Landini MP. Cytomegalovirus-induced immunopathology and its clinical consequences. Herpesviridae. 2011 Apr 7;2(1):6
  47. 47. Simantov R, Lo SK, Gharavi A, Sammaritano LR, Salmon JE, Silverstein RL. Antiphospholipid antibodies activate vascular endothelial cells. Lupus. 1996 Oct;5(5):440-1.
  48. 48. Olsson J, Wikby A, Johansson B, Löfgren S, Nilsson BO, Ferguson FG. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev. 2000 Dec 20;121(1-3):187-201.
  49. 49. Pawelec G, McElhaney JE, Aiello AE, Derhovanessian E. The impact of CMV infection on survival in older humans. Curr Opin Immunol. 2012 Aug;24(4):507-11.
  50. 50. Hadrup SR, Strindhall J, Køllgaard T, Seremet T, Johansson B, Pawelec G, thor Straten P, Wikby A. Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol. 2006 Feb 15;176(4):2645-53.
  51. 51. Roberts ET, Haan MN, Dowd JB, Aiello AE. Cytomegalovirus antibody levels, inflammation, and mortality among elderly Latinos over 9 years of follow-up. Am J Epidemiol. 2010 Aug 15;172(4):363-71.
  52. 52. Berry NJ, Burns DM, Wannamethee G, Grundy JE, Lui SF, Prentice HG, Griffiths PD. Seroepidemiologic studies on the acquisition of antibodies to cytomegalovirus, herpes simplex virus, and human immunodeficiency virus among general hospital patients and those attending a clinic for sexually transmitted diseases. J Med Virol. 1988 Apr;24(4):385-93.
  53. 53. Moro-García MA, Alonso-Arias R, López-Vázquez A, Suárez-García FM, Solano-Jaurrieta JJ, Baltar J, López-Larrea C. Relationship between functional ability in older people, immune system status, and intensity of response to CMV. Age (Dordr). 2012 Apr;34(2):479-95.
  54. 54. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, Nayak L, Moss PA. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol. 2002 Aug 15;169(4):1984-92.
  55. 55. Vescovini R, Biasini C, Telera AR, Basaglia M, Stella A, Magalini F, Bucci L, Monti D, Lazzarotto T, Dal Monte P, Pedrazzoni M, Medici MC, Chezzi C, Franceschi C, Fagnoni FF, Sansoni P. Intense antiextracellular adaptive immune response to human cytomegalovirus in very old subjects with impaired health and cognitive and functional status. J Immunol. 2010 Mar 15;184(6):3242-9.
  56. 56. Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G. Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol. 2004 Apr;39(4):607-13.
  57. 57. Pawelec G, Derhovanessian E. Role of CMV in immune senescence. Virus Res, 2011,157(2):175–9
  58. 58. Ouyang Q, Wagner WM, Zheng W, Wikby A, Remarque EJ, Pawelec G. Dysfunctional CMV-specific CD8(+) T cells accumulate in the elderly. Exp Gerontol. 2004 Apr;39(4):607-13.
  59. 59. Jarvis MA, Nelson JA. Human cytomegalovirus tropism for endothelial cells: not all endothelial cells are created equal. J Virol. 2007 Mar;81(5):2095-101.
  60. 60. eckert CK, Renzaho A, Tervo HM, Krause C, Deegen P, Kühnapfel B, Reddehase MJ, Grzimek NK. Liver sinusoidal endothelial cells are a site of murine cytomegalovirus latency and reactivation. J Virol. 2009 Sep;83(17):8869-84.
  61. 61. Koffron AJ, Hummel M, Patterson BK, Yan S, Kaufman DB, Fryer JP, Stuart FP, Abecassis MI. Cellular localization of latent murine cytomegalovirus. J Virol. 1998 Jan;72(1):95-103.
  62. 62. Gyorkey F, Melnick JL, Guinn GA, Gyorkey P, DeBakey ME. Herpesviridae in the endothelial and smooth muscle cells of the proximal aorta in arteriosclerotic patients. Exp Mol Pathol. 1984 Jun;40(3):328-39.
  63. 63. Hendrix MG, Dormans PH, Kitslaar P, Bosman F, Bruggeman CA. The presence of cytomegalovirus nucleic acids in arterial walls of atherosclerotic and nonatherosclerotic patients. Am J Pathol. 1989 May;134(5):1151-7.
  64. 64. Gredmark-Russ S, Dzabic M, Rahbar A, Wanhainen A, Björck M, Larsson E, Michel JB, Söderberg-Nauclér C. Active cytomegalovirus infection in aortic smooth muscle cells from patients with abdominal aortic aneurysm. J Mol Med (Berl). 2009 Apr;87(4):347-56.
  65. 65. Haarala A, Kähönen M, Lehtimäki T, Aittoniemi J, Jylhävä J, Hutri-Kähönen N, Taittonen L, Laitinen T, Juonala M, Viikari J, Raitakari OT, Hurme M. Relation of high cytomegalovirus antibody titres to blood pressure and brachial artery flow-mediated dilation in young men: the Cardiovascular Risk in Young Finns Study. Clin Exp Immunol. 2012 Feb;167(2):309-16.
  66. 66. Safaie N, Ghotaslou R, Montazer Ghaem H. Seroprevalence of cytomegalovirus in patients with and without coronary artery diseases at Madani Heart Center, Iran. Acta Med Iran. 2010 Nov-Dec;48(6):403-6.
  67. 67. Romo N, Fitó M, Gumá M, Sala J, García C, Ramos R, Muntasell A, Masiá R, Bruguera J, Subirana I, Vila J, de Groot E, Elosua R, Marrugat J, López-Botet M. Association of atherosclerosis with expression of the LILRB1 receptor by human NK and T-cells supports the infectious burden hypothesis. Arterioscler Thromb Vasc Biol. 2011 Oct;31(10):2314-21.
  68. 68. Hsue PY, Hunt PW, Sinclair E, Bredt B, Franklin A, Killian M, Hoh R, Martin JN, McCune JM, Waters DD, Deeks SG. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS. 2006 Nov 28;20(18):2275-83.
  69. 69. Wong BW, Wong D, McManus BM. Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol. 2002 Nov-Dec;11(6):332-8.
  70. 70. Ludwig A, Berkhout T, Moores K, Groot P, Chapman G. Fractalkine is expressed by smooth muscle cells in response to IFN-gamma and TNF-alpha and is modulated by metalloproteinase activity. J Immunol. 2002 Jan 15;168(2):604-12.
  71. 71. olovan-Fritts CA, Spector SA. Endothelial damage from cytomegalovirus-specific host immune response can be prevented by targeted disruption of fractalkine-CX3CR1 interaction. Blood. 2008 Jan 1;111(1):175-82.
  72. 72. ostolakis S, Krambovitis E, Vlata Z, Kochiadakis GE, Baritaki S, Spandidos DA. CX3CR1 receptor is up-regulated in monocytes of coronary artery diseased patients: impact of pre-inflammatory stimuli and renin-angiotensin system modulators. Thromb Res. 2007;121(3):387-95.
  73. 73. Sacre K, Hunt PW, Hsue PY, Maidji E, Martin JN, Deeks SG, Autran B, McCune JM. A role for cytomegalovirus-specific CD4+CX3CR1+ T cells and cytomegalovirus-induced T-cell immunopathology in HIV-associated atherosclerosis. AIDS. 2012 Apr 24;26(7):805-14.
  74. 74. Gordon SN, Cervasi B, Odorizzi P, Silverman R, Aberra F, Ginsberg G, Estes JD, Paiardini M, Frank I, Silvestri G. Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals. J Immunol 2010; 185:5169-79
  75. 75. Fernandez S, Nolan RC, Price P, Krueger R, Wood C, Cameron D, Solomon A, Lewin SR and French MA. Thymic function in severely immunodeficient HIV type 1-infected patients receiving stable and effective antiretroviral therapy. AIDS Res Hum Retroviruses 2006; 22:163-70
  76. 76. Kaufmann GR, Furrer H, Ledergerber B, Perrin L, Opravil M, Vernazza P, Cavassini M, Bernasconi E, Rickenbach M, Hirschel B and Battegay M. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy. Clin Infect Dis 2005; 41:361-72.
  77. 77. Meissner EG, Duus KM, Loomis R, D'Agostin R and Su L. HIV-1 replication and pathogenesis in the human thymus. Curr HIV Res 2003; 1:275-85.
  78. 78. Haynes BF, Markert ML, Sempowski GD, Patel DD and Hale LP. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol 2000; 18:529-60.
  79. 79. Heiden D, Ford N, Wilson D, Rodriguez WR, Margolis T, Janssens B, Bedelu M, Tun N, Goemaere E, Saranchuk P, Sabapathy K, Smithuis F, Luyirika E and Drew WL. Cytomegalovirus retinitis: the neglected disease of the AIDS pandemic. PLoS Med 2007; 4:e334
  80. 80. Docke WD, Prosch S, Fietze E, Kimel V, Zuckermann H, Klug C, Syrbe U, Kruger DH, von Baehr R and Volk HD. Cytomegalovirus reactivation and tumour necrosis factor. Lancet 1994; 343:268-9.
  81. 81. Ownby RL, Kumar AM, Benny Fernandez J, Moleon-Borodowsky I, Gonzalez L, Eisdorfer S, Waldrop-Valverde D and Kumar M. Tumor necrosis factor-alpha levels in HIV-1 seropositive injecting drug users. J NeuroimmunePharmacol 2009; 4:350-8.
  82. 82. Sauce D, Larsen M, Fastenackels S, Duperrier A, Keller M, Grubeck-Loebenstein B, Ferrand C, Debre P, Sidi D and Appay V. Evidence of premature immune aging in patients thymectomized during early childhood. J Clin Invest 2009; 119:3070-8.
  83. 83. Stone SF, Price P and French MA. Cytomegalovirus (CMV)-specific CD8+ T cells in individuals with HIV infection: correlation with protection from CMV disease. J Anti microb Chemother 2006; 57:585-8.
  84. 84. Naeger DM, Martin JN, Sinclair E, Hunt PW, Bangsberg DR, Hecht F, Hsue P, McCune JM, Deeks SG. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS One. 2010 Jan 29;5(1):e8886.
  85. 85. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, Tracy RP, Corey L, Deeks SG. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011 May 15;203(10):1474-83.
  86. 86. Hsue PY, Hunt PW, Sinclair E, Bredt B, Franklin A, Killian M, Hoh R, Martin JN, McCune JM, Waters DD and Deeks SG. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006; 20:2275-83.
  87. 87. Parrinello CM, Sinclair E, Landay AL, Lurain N, Sharrett AR, Gange SJ, Xue X, Hunt PW, Deeks SG, Hodis HN, Kaplan RC. Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. J Infect Dis. 2012 Jun 15;205(12):1788-96.
  88. 88. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007 Jul;92(7):2506-12.
  89. 89. Fisher SD, Miller TL, Lipshultz SE. Impact of HIV and highly active antiretroviral therapy on leukocyte adhesion molecules, arterial inflammation, dyslipidemia, and atherosclerosis. Atherosclerosis. 2006 Mar;185(1):1-11.
  90. 90. Vittecoq D, Escaut L, Chironi G, Teicher E, Monsuez JJ, Andrejak M, Simon A. Coronary heart disease in HIV-infected patients in the highly active antiretroviral treatment era. AIDS. 2003 Apr;17 Suppl 1:S70-6.
  91. 91. Zona S, Raggi P, Bagni P, Orlando G, Carli F, Ligabue G, Scaglioni R, Rossi R, Modena MG, Guaraldi G. Parallel increase of subclinical atherosclerosis and epicardial adipose tissue in patients with HIV. Am Heart J. 2012 Jun;163(6):1024-30.
  92. 92. Tan DB, Fernandez S, French M and Price P. Could natural killer cells compensate for impaired CD4+ T-cell responses to CMV in HIV patients responding to antiretroviral therapy? ClinImmunol 2009; 132:63-70.
  93. 93. Fauci AS, Mavilio D and Kottilil S. NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol 2005; 5:835-43.
  94. 94. Price P, Fernandez S, Tan DB, James IR, Keane NM and French MA. Nadir CD4 T-cell counts continue to influence interferon-gamma responses in HIV patients who began antiretroviral treatment with advanced immunodeficiency. J Acquir Immune DeficSyndr 2008; 49:462-4.
  95. 95. Tan DB, Fernandez S, French M and Price P. Could natural killer cells compensate for impaired CD4+ T-cell responses to CMV in HIV patients responding to antiretroviral therapy? ClinImmunol 2009; 132:63-70.
  96. 96. Fishman JA. Infection in solid-organ transplant recipients. N Eng J Med 2007; 357:2601-14
  97. 97. Peterson PK, Balfour HH Jr, Marker SC, Fryd DS, Howard RJ, Simmons RL. Cytomegalovirus disease in renal allograft recipients: a prospective study of the clinical features, risk factors and impact on renal transplantation. Medicine (Baltimore). 1980 Jul;59(4):283-300.
  98. 98. Helanterä I, Lautenschlager I, Koskinen P. The risk of cytomegalovirus recurrence after kidney transplantation. Transpl Int. 2011 Dec;24(12):1170-8.
  99. 99. Luan FL, Kommareddi M, Ojo AO. Impact of cytomegalovirus disease in D+/R- kidney transplant patients receiving 6 months low-dose valganciclovir prophylaxis. Am J Transplant. 2011 Sep;11(9):1936-42.
  100. 100. Smith JM, Corey L, Bittner R, Finn LS, Healey PJ, Davis CL, McDonald RA. Subclinical viremia increases risk for chronic allograft injury in pediatric renal transplantation. J Am Soc Nephrol. 2010 Sep;21(9):1579-86.
  101. 101. Tong CY, Bakran A, Peiris JS, Muir P, Herrington CS. The association of viral infection and chronic allograft nephropathy with graft dysfunction after renal transplantation. Transplantation. 2002 Aug 27;74(4):576-8.
  102. 102. Jardine AG, Gaston RS, Fellstrom BC, Holdaas H. Prevention of cardiovascular disease in adult recipients of kidney transplants. Lancet. 2011 Oct 15;378(9800):1419-27.
  103. 103. Gómez E, Laurés A, Baltar JM, Melón S, Díez B, de Oña M. Cytomegalovirus replication and "herpesvirus burden" as risk factor of cardiovascular events in the first year after renal transplantation. Transplant Proc. 2005 Nov;37(9):3760-3.

Written By

Patricia Price

Submitted: June 28th, 2012 Published: May 29th, 2013