Effect of Rimantadine on Influenza Virus Replication 1

Abstract

Summary

Rimantadine hydrochloride in concentrations up to 50 μg/ml inhibits the replication of A/WSN influenza virus in MDCK cells without causing visible cytopathic effects. Virus replication was inhibited when the drug was added immediately following infection, but not when added late in the replicative cycle. Rimantadine does not alter the structural integrity of influenza virus as measured by sedimentation profiles of purified virus in linear sucrose gradients. Addition of drug following the viral adsorption period blocked the stimulation of cellular DNA-dependent RNA polymerase II activity observed in untreated infected cells, but had no effect on RNA polymerase II activity isolated from uninfected cell nuclei. Rimantadine present 0-8 hr postinfection inhibited the formation of viral RNA-dependent RNA polymerase activity in infected cells, but when this enzyme was assayed in vitro, rimantadine at concentrations as high as 250 μg/ml did not significantly inhibit polymerase activity. Finally, rimantadine interferes with viral and cellular protein synthesis, but this inhibition appears not to be of sufficient magnitude to account for the antiviral effect of the drug. We conclude that the drug inhibits influenza replication in vitro by acting at a step following viral adsorption and preceding primary transcription of the influenza virus genome.