Enhanced Cytomegalovirus Infection in Atherosclerotic Human Blood Vessels

Abstract

Human cytomegalovirus (CMV) is a possible co-factor in atherogenesis and vascular occlusion, but its ability to actively infect medium and large blood vessels is unclear. A vascular explant model was adapted to investigate CMV infection in human coronary artery, internal mammary artery (IMA), and saphenous vein (SV). Vascular explants were inoculated with CMV Towne or low-passage clinical isolate and examined in situ for CMV cytopathic effect and immediate-early and early antigens, as indicators of active infection. At 5 to 7 days after inoculation, we found that CMV Towne actively infected eight of eight different atherosclerotic blood vessel explants (coronary artery, n = 4; SV and IMA grafts, n = 4), whereas it only infected 2 of 14 nonatherosclerotic blood vessel explants (SV, n = 10; IMA, n = 4) (P = 0.001). The CMV clinical isolate actively infected none of six sets of nonatherosclerotic SV explants at 5 to 7 days after inoculation. The active CMV infections involved adventitial and, less frequently, intimal cells. A small subset of infected cells in atherosclerotic tissue expresses the endothelial cell marker CD31. Smooth muscle cells residing in both atherosclerotic and nonatherosclerotic blood vessels were free of active CMV infections even after all vascular tissue layers were exposed to the virus. In contrast, active CMV Towne infection was evident at 2 days after inoculation in smooth muscle cells and endothelial cells previously isolated from the SV tissues. We conclude that active CMV infection is enhanced in atherosclerotic blood vessels compared to atherosclerosis-free vascular equivalents, and this viral activity is restricted to subpopulations of intimal and adventitial cells.

Expansion of the NKG2C+ Natural Killer–Cell Subset Is Associated With High-Risk Carotid Atherosclerotic Plaques in Seropositive Patients for Human Cytomegalovirus

“…In this context, HCMV is a usual suspect, and several hypothetical mechanisms have been proposed to explain its contribution in the pathogenesis of atherosclerosis, for example, induction of endothelial damage, homing of latently infected monocytes, direct infection of different cell types in the vessel wall, and triggering of antiviral immune responses. [20][21][22][23] Presumably, the impact of HCMV on atherosclerosis development may be particularly relevant when the latent infection is inefficiently controlled, as observed in immunosuppressed patients. 24 In this regard, NK cells are involved in the immune defense against HCMV together with T lymphocytes.…”

Significant Increase in 1-Year Posttransplant Renal Arterial Index Predicts Graft Loss

“…Moreover, Fearon et al (14) reported that CMV seropositivity and the lack of prophylaxis against CMV correlate with negative remodeling of coronary arteries. Finally, both animal models and epidemiologic studies suggest a role for CMV in atherogenesis (15)(16)(17). Concordant with these data, CMV may contribute to endothelial dysfunction and vascular aging in renal transplant patients.…”

Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8+T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons

“…Tumor necrosis factor alpha can also increase the toxicity of ␤-amyloid (4) as well as stimulate smooth muscle cell proliferation, a key event in the development of atherosclerosis. As CMV is postulated to reside in endothelial cells during latency and has been detected in atherosclerotic plaques (26), the latter mechanism may be of particular relevance in elderly persons with chronic CMV infections.…”