The cost of replication fidelity in human immunodeficiency virus type 1

Mutation rates should be governed by at least three evolutionary factors: the need for beneficial mutations, the benefit of minimizing the mutational load and the cost of replication fidelity. RNA viruses show high mutation rates compared with DNA micro-organisms, and recent findings suggest that the cost of fidelity might play a role in the evolution of increased mutation rates. Here, by analysing previously published data from HIV-1 reverse transcriptase in vitro assays, we show a trade-off between enzymatic accuracy and the maximum rate of polymerization, thus providing a biochemical basis for the fitness cost of fidelity in HIV-1. This trade-off seems to be related to inefficient extension of mispairs, which increases fidelity at the expense of the polymerization rate. Since in RNA viruses fast replication is critical for survival, this could impose a high cost of fidelity and favour the evolution of high mutation rates.