Nucleosides for the treatment of respiratory RNA virus infections

Jordan, Paul C; Stevens, Sarah K; Deval, Jerome

Studies evaluating the mechanism of action of ribavirin have produced contradictory results. It is usually acknowledged that ribavirin exerts its main effect through its monophosphate metabolite by inhibiting the host inosine monophosphate dehydrogenase (IMPDH) enzyme, leading to depletion of intracellular GTP pools, which results in indirect inhibition of RNA synthesis during viral replication (for review 111 ). The nucleoside form of ribavirin is also believed to enhance T-cell-mediated immune response through increased expression of interferon-gamma and tumor necrosis factor-alpha. 111 In addition, it has been proposed that prolonged replication of PV in the presence of ribavirin increases the viral mutation frequency and decreases infectivity. 112 One hypothesis is that the mutagenic effect of ribavirin is caused by its triphosphate form that is recognized by the viral RNA polymerase. 112 Once incorporated into the viral genome, ribavirin monophosphate could equally base pair with cytidine and uridine, therefore causing random mutations throughout the viral genome.