Mechanism and specificity of action of ribavirin

Abstract

Ribavirin at a concentration of 30 mug/ml added immediately after infection completely inhibited influenza A/Port Chalmers/1/73 (H(3)N(2)) virus hemagglutinin production in infected MDCK cells. Under these conditions, host cell protein synthesis was inhibited by only 10 to 20%. Polyacrylamide gel electrophoresis of [(35)S]methionine-labeled material from virus-infected cultures confirmed that ribavirin inhibited viral but not host cell protein synthesis. In parallel experiments, actinomycin D also preferentially inhibited viral protein synthesis. The possibility that ribavirin inhibited viral protein synthesis as a result of general inhibition of ribonucleic acid synthesis was therefore examined. In uninfected cells, ribavirin at 30 mug/ml inhibited the incorporation of [(14)C]inosine or [(3)H]uridine into ribonucleic acid but stimulated the incorporation of [(3)H]guanosine. The effects noted are consistent with an inhibition of the host cell enzyme inosine 5'-monophosphate dehydrogenase. This suggestion is supported by the finding that addition of guanosine, but not inosine, to the culture medium substantially reversed the antiviral effect of ribavirin. There was no separation between the concentration of ribavirin causing inhibition of influenza A viral protein synthesis or inhibition of MDCK cell ribonucleic acid synthesis, suggesting that ribavirin is not specifically antiviral in this system but inhibits viral protein synthesis as a result of the general inhibition of ribonucleic acid synthesis.