Cytomegalovirus Infection Is Associated With Cardiac Allograft Rejection and Atherosclerosis

Grattan, Mark T.; Moreno-Cabral, Carlos E.; Starnes, Vaughn A.; Oyer, P E; Stinson, Edward B.; Shumway, Norman E.

doi:10.1001/jama.1989.03420240075030

Cited by 768 publications

(155 citation statements)

References 23 publications

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“…HCMV seropositivity is an important risk factor for graft and solid-organ transplant failure (28). In the case of heart transplantation, HCMV nearly doubles the 5-year rate of cardiac graft rejections as a consequence of transplant vascular arteriosclerosis (29). Additionally, HCMV persistence in healthy individuals is associated with an increased risk of age-related vascular pathologies, including atherosclerosis and restenosis, and correlates positively with greater risks for frailty and cardiac mortality (27,(30)(31)(32)(33)(34)(35)(36).…”

mentioning

confidence: 99%

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Bughio

Umashankar

Wilson

et al. 2015

J Virol

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Endothelial cells (ECs) are a critical target of viruses, and infection of the endothelium represents a defining point in viral pathogenesis. Human cytomegalovirus (HCMV), the prototypical betaherpesvirus, encodes proteins specialized for entry into ECs and delivery of the genome to the nuclei of ECs. Virus strains competent to enter ECs replicate with differing efficiencies, suggesting that the virus encodes genes for postentry tropism in ECs. We previously reported a specific requirement for the UL133/8 locus of HCMV for replication in ECs. The UL133/8 locus harbors four genes: UL133, UL135, UL136, and UL138. In this study, we find that while UL133 and UL138 are dispensable for replication in ECs, both UL135 and UL136 are important. These genes are not required for virus entry or the expression of viral genes. The phenotypes associated with disruption of either gene reflect phenotypes observed for the UL133/8 NULL virus, which lacks the entire UL133/8 locus, but are largely distinct from one another. Viruses lacking UL135 fail to properly envelop capsids in the cytoplasm, produce fewer dense bodies (DB) than the wild-type (WT) virus, and are unable to incorporate viral products into multivesicular bodies (MVB). Viruses lacking UL136 also fail to properly envelop virions and produce larger dense bodies than the WT virus. Our results indicate roles for the UL135 and UL136 proteins in commandeering host membrane-trafficking pathways for virus maturation. UL135 and UL136 represent the first HCMV genes crucial for early-to late-stage tropism in ECs. H uman cytomegalovirus (HCMV) is a ubiquitous herpesvirus with 50 to 99% seroprevalence in the global population. Like all herpesviruses, HCMV persists for the lifetime of the host by way of latent infection (1-3). The persistence of HCMV is asymptomatic in immunocompetent individuals and is characterized by states of subclinical reactivation from latency and low-level virus shedding (1). However, in immunocompromised hosts, HCMV causes significant morbidity and mortality. Of particular concern are stem cell and solid-organ transplant patients, HIV/AIDS patients, and cancer patients undergoing chemotherapy or radiation regimens (4, 5). Additionally, HCMV is the leading cause of infectious disease-related birth defects in the United States, affecting 1 in 150 children born in the United States and most commonly resulting in mild to severe hearing loss (6). While CMV infection of seronegative women during pregnancy poses the most significant risk for severe sequelae in infants (microcephaly, cerebral palsy, and severe hearing loss or cognitive deficits), as many as 75% of congenital infections occur in infants whose mothers were seropositive at the time of conception, indicating that these infections result from reinfection or reactivation (7). Finally, the persistence of HCMV is increasingly associated with age-related pathologies, even when overt clinical symptoms are absent. Agerelated pathologies include vascular disease, immune dysfunction, and frailty (8-13)...

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mentioning

confidence: 99%

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Bughio

Umashankar

Wilson

et al. 2015

J Virol

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“…In recipients of cardiac transplants CMV has been historically linked to CAV [4]. It is interesting that CMV levels correlate with development of CAV and plasma ADMA levels correlate with CMV viremia.…”

Section: Role Of CMVmentioning

confidence: 99%

“…The mechanisms underlying the process are poorly understood but there exists a definite link. As early as 1989, it was noted that CMV infection led to increased frequency of rejection and CAV [4]. Endothelial dysfunction has been described as the major force in CMV induced CAV …”

Section: Introductionmentioning

confidence: 99%

Role of Oxidative Stress in Cardiac Allograft Vasculopathy

Nair¹,

Góngora²,

Reynolds³

2013

OJOTS

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Cardiac Allograft Vasculopathy, an accelerated form of arterial occlusive disease, is the major cause of death in the long-term after heart transplantation. Multiple factors influence the initiation and progression of CAV. These include ischemia-reperfusion, dyslipidemia, insulin resistance, and hypertension due to the use of immunosuppressive agents, the direct effects of immunosuppressive agents on endothelial function, and viruses (CMV). Impaired endothelial function reflects abnormalities in the production or activity of several vasoactive substances. Disruption of the nitric oxide synthase (NOS) pathway leads to changes in vascular reactivity, structure, and interaction with circulating blood components. Since endothelium-derived nitric oxide (NO) suppresses vascular cell proliferation and vascular inflammation, a deficit in vascular NO facilitates development of CAV. The link between oxidative stress and CAV largely exists in the balance between free radical superoxide   2 O  generation and NO production. This review focuses on identifying the oxidative stress factors affecting CAV.

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“…14,15 Additional evidence of CMV causing a vasculopathy is derived from the evidence of association of CMV and advanced progression of atherosclerosis and vasculopathy in hearttransplant recipients. 16 …”

Section: Herpesvirus Familymentioning

confidence: 99%

‘Infectious Burden’ - New Insights into Stroke Prevention

Luna¹,

Elkind²

2010

European Neurological Review

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Atherosclerosis is a complex inflammatory disease process of the arterial vessels.1 Chronic and acute infections have been implicated as risk factors that increase the risk of stroke, myocardial infarction (MI) and other vascular events. However, no single pathogen is likely to be responsible for elevated vascular risk. Pathogens as Risk Factors for Atherosclerosis Chlamydia pneumoniaeChlamydia pneumoniae is a common respiratory pathogen believed to be responsible for approximately 10% of non-hospital-acquired pneumonias. 3 C. pneumoniae is one of the best-studied organisms believed to be associated with cardiovascular disease. Studies that have evaluated human samples of atherosclerotic lesions using electron microscopy, molecular DNA methods and immunostaining techniques have identified C. pneumoniae in coronary, carotid, aortic and popliteal plaque. 4 The majority of these studies have identified pathogen DNA or antigen only; however, a few studies have isolated viable C. pneumoniae organisms. 5,6 C. pneumoniae has been identified in both early-and late-stage fibrous plaque and, in particular, in carotid and cerebral arterial vessels. 7-9Herpesvirus FamilyHerpesviruses were initially identified as potential causes of atherosclerosis in animal models, and they have been the target of investigations into the association of infectious agents and atherosclerosis since then. 10 The most thoroughly investigated of the eight herpesvirus known to commonly infect humans are herpes simplex virus 1 (HSV1), HSV2 and cytomegalovirus (CMV). HSV1infection has been associated with accelerated atheroma formation in apolipoprotein E -/-(apoE -/-) mice, with a reduction in progression when treated with antiviral therapies. 11 HSV1 DNA has been found in some but not all samples of carotid atherosclerotic lesions. 12,13 The recurrent outbreaks associated with HSV infection and high population prevalence of exposure have made it an interesting target for epidemiological study. 'Infectious Burden' -New Insights into Stroke PreventionBrain Trauma Stroke AbstractChronic and acute infections have been implicated as risk factors that increase the risk of stroke, myocardial infarction (MI) and other vascular events. The lack of consistency among studies attempting to link exposure to infectious pathogens and stroke risk provides empirical evidence that a single pathogen is likely not responsible for stroke. Reconsidering exposure as an 'infectious burden' (IB) aligns with our understanding that the totality of pro-inflammatory agents can contribute to atherosclerosis and vascular risk. We define IB as the cumulative life-course exposure to infectious agents that elicit strong inflammatory responses and review the varied approaches to operationalising this measure.There is promising research investigating the role of acute and chronic IB suggesting that there may be a causal role of pathogens in atherosclerotic progression and plaque destabilisation to negatively affect vascular risk; however, the evidence is preliminary.

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Cytomegalovirus Infection Is Associated With Cardiac Allograft Rejection and Atherosclerosis

Cited by 768 publications

References 23 publications

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Human Cytomegalovirus UL135 and UL136 Genes Are Required for Postentry Tropism in Endothelial Cells

Role of Oxidative Stress in Cardiac Allograft Vasculopathy

‘Infectious Burden’ - New Insights into Stroke Prevention

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