Error catastrophe and antiviral strategy

The term “error catastrophe,” originally introduced in the theory of molecular evolution (1), has become fashionable among virologists. In a recent paper in PNAS (2), it was suggested, on the basis of quantitative sequence studies, that ribavirin, a common antiviral drug, by its mutagenic action drives poliovirus into an error catastrophe of replication, thereby turning a productive infection into an abortive one. Previous studies by Loeb and his group (3, 4) on the AIDS virus (HIV) and by Domingo, Holland, and coworkers (5, 6) on foot-and-mouth disease virus (FMDV) have led to similar conclusions, suggesting a paradigm shift in antiviral strategies (7). A recent issue of PNAS presents a paper by Grande-Perez et al. (8), which deals with the “molecular indetermination in the transition to error catastrophe,” shedding light on the complexity of the mechanisms involved in virus infection and stressing the need for a careful molecular analysis of the detail, which may differ greatly from one virus to another. Because of its practical relevance for developing potent antiviral drugs and, beyond that, its general importance for an understanding of molecular evolution, this commentary will highlight the theoretical basis and point out the kind of conclusions that can be drawn in discussing experimental results. The term error catastrophe is of a descriptive nature and lacks a clear-cut definition. A catastrophe is usually triggered if certain tolerances are exceeded. For replication, there is indeed such a limiting value of error or mutation rate that must not be surpassed if the wild type is to be kept stable. We call this limit the “error threshold.” Why is it a sharply defined limit? Why does the efficiency of replication not vary monotonically with the error rate? The information stored in the genomic sequence melts like ice at 0°C. This comparison is …