USE OF THE YELLOW-FEVER VIRUS-VACCINE STRAIN 17D FOR THE STUDY OF STRATEGIES FOR THE TREATMENT OF YELLOW-FEVER VIRUS-INFECTIONS

We have employed the attenuated vaccine strain 17D of yellow fever vir us (YFV) to evaluate the inhibitory effect of a selected series of com pounds on YFV in Vero cells. Use of the vaccine strain does not requir e high-level microbiological containment facilities and should allow e xtensive screening. In addition, YFV may serve as a model for other fl aviviruses including hepatitis C virus (HCV), and thus strategies for the treatment of YFV infections may apply to flavivirus infections in general. In the present study, several compounds belonging to differen t classes of nucleoside analogues and polyanions were evaluated for th eir inhibitory effect on the replication of YFV. Compounds that are ta rgeted at: (i) IMP dehydrogenase (ribavirin, EICAR, tiazofurin, selena zofurin and mycophenolic acid), (ii) OMP decarboxylase (pyrazofurin an d 6-azauridine), (iii) CTP synthetase (carbodine and cyclopentenyl cyt osine), (iv) dihydrofolate reductase (methotrexate) and the (v) sulfat ed polymers (dextran sulfate and PAVAS) proved inhibitory to the repli cation of YFV. Mycophenolic acid (EC(50): 0.08 mu g/ml), EICAR (EC(50) : 0.8 mu g/ml) and methotrexate (EC(50): 0.07 mu g/ml) were the most e ffective. The finding that EICAR and mycophenolic acid, despite their potent anti-YFV activity, had little or no effect on the replication o f the bunyavirus Punta Toro or herpes simplex virus in Vero cells, ind icates that their anti-YFV activity is rather specific and does not me rely result from cytotoxicity. Inhibitors of S-adenosylhomocysteine hy drolase (SAH hydrolase) and thymidylate synthase were found to be devo id of anti-YFV activity.