title: Interrelationship between HIV-1 fitness and mutation rate.
abstract: 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.
authors.affiliation: Institute for Molecular Virology, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dapp
authors.forename: Richard H
authors.initials: RH
authors.lastname: Heineman
authors.forename: Louis M
authors.initials: LM
authors.lastname: Mansky
mesh_terms: D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009154:Mutation; D059645:Mutation Rate; D010641:Phenotype; D014779:Virus Replication
chemical_list: C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase