Differences in replication fidelity, as well as mutator and antimutator strains, suggest that virus mutation rates are heritable and prone to natural selection. Human immunodeficiency virus type 1 (HIV-1) has many distinct advantages for the study of mutation rate optimization given the wealth of structural and biochemical data on HIV-1 reverse transcriptase (RT) and mutants. In this study, we conducted parallel analyses of mutation rate and viral fitness. In particular, a panel of 10 RT mutants-most having drug resistance phenotypes-was analyzed for their effects on viral fidelity and fitness. Fidelity differences were measured using single-cycle vector assays, while fitness differences were identified using ex vivo head-to-head competition assays. As anticipated, virus mutants possessing either higher or lower fidelity had a corresponding loss in fitness. While the virus panel was not chosen randomly, it is interesting that it included more viruses possessing a mutator phenotype rather than viruses possessing an antimutator phenotype. These observations provide the first description of an interrelationship between HIV-1 fitness and mutation rate and support the conclusion that mutator and antimutator phenotypes correlate with reduced viral fitness. In addition, the findings here help support a model in which fidelity comes at a cost of replication kinetics and may help explain why retroviruses like HIV-1 and RNA viruses maintain replication fidelity near the extinction threshold.

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