Inhibitory effect of papaverine on RNA and protein synthesis of vesicular stomatitis virus.

Papaverine, an inhibitor of cAMP phosphodiesterase, reduced yields of infectious vesicular stomatitis virus in HEp-2 cells approximately 100-fold if added to cultures at a concentration of 30 microM before and after virus infection. The extent of papaverine-induced suppression of viral growth was dependent on drug dose and treatment regimen. Cells progressively recovered their viral permissive state after removal of drug. The cyclic nucleotide, cGMP, nullified the inhibitory effect of papaverine if added to cells during drug treatment. Pulse labeling experiments with [35S]methionine showed that papaverine compromises production of all virus-specific proteins in infected cells without adversely affecting host cell protein synthesis. Treatment of cells with papaverine strongly inhibited the production of viral RNA and both cellular RNA and DNA. It was found that VSV causes an immediate but transient stimulation of DNA synthesis in HEp-2 cells which is prevented by papaverine treatment. This drug also selectively blocked primary transcription of VSV in vivo and to a lesser extent in vitro RNA polymerase activity of the virion-bound transcriptase. The finding that papaverine has a strong inhibitory effect on viral biosynthesis including early transcription suggests that VSV replication may depend on host factors that regulate intracellular levels of cyclic nucleotides such as cAMP.