DIRECT INDUCTION OF CLASS-II MOLECULES BY CYTOMEGALOVIRUS IN RAT-HEART MICROVASCULAR ENDOTHELIAL-CELLS IS INHIBITED BY GANCICLOVIR (DHPG)

It has been demonstrated both in vivo and in vitro that cytomegaloviru s regulates not only MHC class I but also class II antigen expression on vascular endothelial cells. The CMV-linked MHC induction is believe d to be involved in acute rejection mechanisms and chronic vasculopath y after transplantation. In this study, we have investigated the effec t of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG; ganciclovir) on C MV-induced class II expression in cultured rat heart microvascular end othelial cells. Two sets of cultured endothelial cells were infected w ith rat CMV. One of the sets was treated with various concentrations o f DHPG and the other set was left untreated. MHC class II antigen expr ession on the cells was demonstrated by mAbs, by immunoperoxidase (IF) technique, and by FACS. Class II expression was maximal on CMV-infect ed cells 4-7 days after infection when 77.5+/-14.5% of the endothelial cells expressed class II in IP staining. DHPG inhibited the induction of class II, but the inhibitory effect was dependent upon the drug co ncentration. With increasing concentrations of DHPG (0, 1, 10, 100, an d 1000 mu g/ml), as demonstrated by IP staining (surface and intracell ular expression), the frequency of class II-positive cells decreased f rom 77.5+/-14.5% to 58.0+/-15.0%, 36.0+/-23.0%, 3.0+/-3.0%, and 0+/-0% , respectively. By FACS (surface expression), the number of class II p ositive cells remained somewhat lower, but decreased similarly with in creasing concentrations of DHPG (from 37.8+/-1.1% to 6.2+/-3.1%) (surf ace expression). Also, the intensity of expression decreased concomita ntly. These results suggest that DHPG inhibits CMV-induced class II ex pression via inhibition of CMV DNA polymerase.