Cytomegalovirus burden improves a predictive model identifying measures of vascular risk in renal transplant recipients and healthy adults

Abstract

Cytomegalovirus (CMV) has been implicated in vascular pathologies and may warrant inclusion in cardiovascular predictive algorithms. We addressed this in healthy older adults and renal transplant recipients (RTR) as they retain a high burden of CMV. RTR (n = 45) stable more than 2 years after transplantation and 58 age‐matched healthy adults were assessed. Plasma inflammatory biomarkers (soluble isoform of the interferon‐β receptor [sIFNAR2], soluble tumour necrosis factorreceptor‐1 [sTNFR1], soluble cluster of differentiation 14 [sCD14], C reactive protein, P‐selectin, intracellular cell adhesion molecule‐1, vascular cell adhesion molecule‐1), and measures of CMV burden (antibodies, saliva CMV DNA, and interferon γ responses to CMV) were assessed in 2014 and evaluated in 2017 as predictors of vascular health—defined using flow‐mediated dilatation (FMD), pulse wave velocity (PWV), and augmentation indices (Aix@ 75). Linear regression models adjusted for age, sex, and body mass index (BMI) were optimized to identify risk factors. In 2017, RTR had inferior vascular health marked by impaired FMD and PWV. Detectable CMV DNA (P = .02) was associated with impaired FMD, whilst CMV glycoprotein B (gB) antibody attenuated this effect (P = .03) (adjusted R2 = .42). In healthy adults, the optimal model for predicting FMD (R2 =.22) incorporated high P‐selectin (P = .03) and low ICAM‐1 (P = .03) levels with no significant impact of CMV. Elevated sIFNAR2 (P = .04) and gB antibody (P = .06) levels predicted increasing Aix@ 75 (poor vascular health) in healthy adults (R2 = .4), whilst optimal models for RTR (R2 = .37) linked low sIFNAR2 and CMV IE‐1 antibody levels with lower Aix@ 75 (better vascular health). CMV IE‐1 antibody was also protective in relation to PWV in healthy adults (R2 = .55). Overall, measures of active CMV replication were more predictive of impaired FMD in RTR than standard biomarkers, but increased CMV gB antibodies may be protective.

Sequencing Directly from Clinical Specimens Reveals Genetic Variations in HCMV-Encoded Chemokine Receptor US28 That May Influence Antibody Levels and Interactions with Human Chemokines

“…This could begin with R267K, as the variant was associated with increased gB-reactive antibody levels in RTR and a healthier FMD (i.e., better endothelial function). Accordingly, a previous study of the same cohort revealed that levels of gB-reactive antibodies were protective of FMD, as assessed in a 3-year follow up ( 40 ). Our data suggest that variants carrying R267K may promote this protective response.…”

“…Ultrasonography was used to assess FMD of the brachial artery after 10 min of rest in Australian RTR and healthy controls ( 40 ). FMD assesses the ability of the larger conduit artery to respond to shear stress via endothelial-dependent and endothelial-independent mechanisms.…”

Cytomegalovirus may influence vascular endothelial health in Indonesian HIV-infected patients after 5 years on ART

“…FMD associated inversely with levels of sTNFR in healthy controls, with a weak protective effect of gB antibodies. gB also marked protection in our search for biomarkers that predict FMD measured in Australian renal transplant recipients after an interval of three years [ 22 ]. The association is plausible because CMV gB is considered a protective antigen based on its critical role in mediating viral-host cell fusion and thus viral entry.…”

Human Cytomegalovirus-Encoded microRNAs Can Be Found in Saliva Samples from Renal Transplant Recipients

“…This may reflect the transient expression of HCMV DNA in clinical samples. T-cell responses to HCMV IE-1 have been linked with frequent reactivations of HCMV as IE-1 is the first protein expressed during viral replication, but they build over time and so are elevated in HIV patients stable on antiretroviral therapy (ART) [ 7 ]. Our results would be consistent with persistent low-level HCMV replication in the acinar cells of the salivary gland, with episodic outbreaks stimulating systemic responses to HCMV IE-1.…”

“…Accordingly, renal transplant recipients (RTR) have higher levels of circulating antibodies than the general population [ 6 ]. Interferon γ-producing T-cells, particularly those specific for HCMV Immediate Early 1 (IE-1) antigen, are also increased in RTR [ 7 ]. Responses to this antigen are also elevated in HIV patients [ 8 ] and are thought to reflect frequent reactivations of HCMV as the antigen is produced in the earliest stages of the replicative cycle [ 9 ].…”