STRAIN SPECIFIC EFFECTS OF CYTOMEGALOVIRUS ON ENDOTHELIAL CELLS: IMPLICATIONS FOR INVESTIGATING THE RELATIONSHIP BETWEEN CMV AND CARDIAC ALLOGRAFT VASCULOPATHY1

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Abstract
Cytomegalovirus (CMV) has been associated with the development of chronic allograft rejection. Attempts to delineate pathogenetic mechanisms for this association have characteristically used well-established laboratory strains for in vitro investigation and rodent strains for in vivo studies. There is substantial genetic heterogeneity not only among different laboratory strains, but also between laboratory strains and clinical isolates, and genetic differences between human and animal strains are profound. Given these genetic differences, one would anticipate differences in biological activity between strains. Vascular endothelial cells were infected with two laboratory strains of CMV (Towne and AD-169) as well as two individual clinical CMV isolates, after genetic typing with six segments of the genome (including early and late genes). mRNA expression coding for a panel of mesenchymal growth factors was studied using quantitative reverse transcription, polymerase chain reaction. Major histocompatibility complex (MHC) expression was investigated using flow cytometry. There was substantial genetic variability between clinical and laboratory isolates. There did not appear to be differences in overall infectivity by the different strains as determined by expression of immediate-early antigen at 24 hours (5-10% of endothelial cells positive for immediate-early. Two growth factors, platelet-derived growth factor-A and basic fibroblast growth factor were augmented by one of the two clinical strains of CMV (Clin 2) (P=0.0091 and P=0.0018, respectively). Transforming growth factor -α and insulin-like growth factor expression were significantly reduced by both clinical strains and AD-169. Two other growth factors, heparin-binding epidermal growth factor and transforming growth factor-β were not altered by infection with any strain. No strain altered MHC class II expression. MHC class I expression was increased with one of the two clinical strains (Clin 1, P=0.0006) and decreased by AD-169 (P=0.0016). Clin 2 and Towne had no effect on MHC class I expression. These data demonstrate that the genetic heterogeneity of CMV is associated with differences in transplant-relevant biologic activity even among clinical isolates. The relationship between CMV and chronic rejection may be difficult to determine given the heterogeneous nature of this complex virus.

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