CYTOMEGALOVIRUS INFECTION-ENHANCED ALLOGRAFT ARTERIOSCLEROSIS IS PREVENTED BY DHPG PROPHYLAXIS IN THE RAT

Background Major risk factors for accelerated allograft arterioscleros is include humoral and cellular immune response, hyperlipidemia, and v iral infections. We demonstrated earlier that rat cytomegalovirus (RCM V) infection doubles smooth muscle cell proliferation and intimal thic kening of rat aortic allografts. In this study, the effects of 9-(1,3- dihydroxy-2-propoxymethyl)guanine (DHPG) on RCMV-enhanced rat allograf t arteriosclerosis are investigated. Methods and Results Aortic allogr afts from the DA to the WF rat strain were used. The recipients were i noculated with 10(5) plaque-forming units of RCMV 1 day after transpla ntation. Two groups of RCMV-infected rats were treated with DHPG with an initial dose of 20 mg/kg IP and a maintenance dose of 10 mg/kg IP t wice a day for a period of 14 days. In the DHPG prophylaxis group (n=2 2), the drug administration started 1 day before infection, and in the DHPG treatment group (n=17), 7 days after infection. One group of inf ected rats was left untreated (n=21). The grafts were removed 7 and 14 days and 1, 3, and 6 months after transplantation. In the DHPG prophy laxis group, no virus could be recovered by plaque assays. In the trea tment group, 50% of rats were virus-positive at 1 month and 40% at 3 m onths. DHPG prophylaxis prevented the infiltration of inflammatory cel ls and their proliferation in the adventitia of RCMV-infected recipien ts (P<.01), with a 60% reduction in the interleukin-2 receptor express ion (P<.05) and a 30% decrease in major histocompatibility complex cla ss II expression (P=NS). DHPG prophylaxis did not significantly alter the levels of insulin-like growth factor-1, epidermal growth factor, p latelet-derived growth factor-BB, transforming growth factor-beta(1), acidic fibroblast growth factor, and basic fibroblast growth factor me ssages in the allograft vascular wall. Early media necrosis was reduce d. Arteriosclerotic alterations and proliferation of smooth muscle cel ls were both reduced 50% to 70% by DHPG prophylaxis (P<.05 at 3 months ). The responses in the DHPG treatment group were quite similar but le ss impressive and statistically nonsignificant. Conclusions We conside r it likely that DHPG inhibits arteriosclerotic alterations primarily by reducing the infectious virus and thereby the inflammatory response in the allograft vascular wall; another possibility is a direct antip roliferative effect on smooth muscle cell replication. A dose-dependen t inhibitory effect of DHPG on smooth muscle cell replication was reco rded in an in vitro study.