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Objective: Cytomegalovirus (CMV) has been epidemiologically associated with multiple disease processes including coronary, carotid and cardiac graft atherosclerosis. An early initiating event in atherogenesis is the uptake by macrophages of oxidized low-density lipoproteins (OxLDL) via the scavenger receptor, CD36. Because CMV can activate host-cell gene transcription, we hypothesized that CMV may upregulate CD36 expression., Methods and Results: THP-1 monocyte/macrophage cells were treated with Davis strain CMV and cell surface CD36 expression measured by flow cytometry. Virus challenge increased the percentage of cells expressing CD36 from 21.8 +/- 1.7 to 48.2 +/- 4.0% (mean +/- S.D. for three experiments, P=0.0005); CD36 mRNA accumulation was increased by CMV treatment as determined by reverse transcription-polymerase chain reaction. Viral challenge also upregulated the mitogen-activated protein kinase p38; further, the specific p38 inhibitor, SB203580, reversed the CMV-induced CD36 cell surface expression from 57.2% of cells to baseline levels (29.0 and 30.1% for SB203580 treated and control cells, respectively; P=0.001). Treatment with virus also stimulated uptake of OxLDL: microscopically, virus-treated cells had a mean of 32 +/- 4.0 lipid vacuoles compared with 20 +/- 1.3 for control cells (P=0.01)., Conclusions: These findings suggest that CMV-induced CD36 expression is one mechanism through which CMV may promote atherosclerosis. Other CMV-associated atherogenic mechanisms may exist; additional investigation is necessary.

Background: Seropositivity to cytomegalovirus (CMV) and elevated C-reactive protein (CRP) may jointly predict increased mortality rates in patients with coronary artery disease (CAD). Therapy with statins reduces lipid levels but may also have other beneficial (eg, antiinflammatory) effects. This study prospectively evaluated the effect of statins on CMV-and CRP-associated death among patients with significant, angiographically defined CAD., Methods and Results: We monitored 2315 patients with angiographically significant CAD (stenosis > or =70%) for an average of 2.4 years (maximum, 5.8 years). Anti-CMV IgG antibody levels and CRP concentrations were measured at baseline, and statin prescription was recorded. As previously reported, mortality rate was higher for CMV seropositivity (+) with high CRP (hazard ratio [HR], 2.0) and lower for statins (HR, 0.50). Compared with CMV(-)/low CRP (mortality rate, 5% with statin versus 4% without statin), the protective effect of statin therapy was markedly greater for CMV(+)/low CRP (mortality rate, 2% versus 7%; HR, 0.44; 95% CI, 0.16 to 1.3), CMV negative (-)/high CRP (mortality rate, 1% versus 8%; HR, 0.16), and CMV(+)/high CRP (mortality rate, 6% versus 17%; HR, 0.42; 95% CI, 0.25 to 0.70). After adjustment, interactions were found for statin therapy with CMV(+)/low CRP (P for interaction=0.065), CMV(-)/high CRP (P for interaction=0.051), and CMV(+)/high CRP (P for interaction=0.024)., Conclusions: The survival benefit of statins interacted with CMV seropositivity and high CRP to significantly reduce mortality rates among patients with CAD. This finding supports the hypothesis that statins have beneficial, "lipid-independent," antiinflammatory effects. The mechanism of statin benefit associated with CMV seropositivity remains to be determined.