Interrelationship between HIV-1 Fitness and Mutation Rate

JOURNAL OF MOLECULAR BIOLOGY

卷:425

Article

Dapp, Michael J.^1,3,4  Heineman, Richard H.^1,2  Mansky, Louis M.^1,2,3,4,5 

[1] Univ Minnesota, Inst Mol Virol, Acad Hlth Ctr, Minneapolis, MN 55455 USA

[2] Univ Minnesota, Sch Dent, Minnesota Craniofacial Res Training Program, Dept Diagnost & Biol Sci, Minneapolis, MN 55455 USA

[3] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA

[4] Univ Minnesota, Sch Med, Pharmacol Grad Program, Minneapolis, MN 55455 USA

[5] Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA

关键词: retrovirus;    lentivirus;    evolution;    mutation;    fitness;   

DOI  :  10.1016/j.jmb.2012.10.009

来源: Elsevier

【 摘 要 】

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 nnutator 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. (C) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free