FIG. 1.

Possible mechanism for BFA inhibition of poliovirus RNA replication, first proposed by Maynell et al. (30) and supported by our observations in the cell-free system. The budding of nascent transport vesicles at several steps in secretory transport is dependent on the assembly of clathrin or coatomer complexes upon the budding donor membrane face (38, 41). This assembly is catalyzed by ARF-GTP, and disassembly of the coat on the fully formed vesicle occurs upon GTP hydrolysis. ARF can be recycled by a GEF, which is inhibited by BFA. Thus, the drug is an indirect inhibitor of transport vesicle budding. Because poliovirus RNA replication is strongly associated with (but not necessarily dependent on) the vesicularization of secretory organelle membranes, this process may be dependent on the BFA-sensitive mechanism for transport vesicle synthesis. Infection may cause a stimulation in the process, and/or a block in fusion of vesicles to target membranes, causing the disassembly of these organelles and the accumulation of virally induced vesicles. If this process is required for optimal levels of RNA replication to occur, then BFA may act as an indirect inhibitor of replication in the cell-free system and in the infected cell.