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.