Mutation Rates and Intrinsic Fidelity of Retroviral Reverse Transcriptases

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2011 Oct 14

PMID 21994586

Citations 65

Authors

Luis Menendez-Arias

Affiliations

Soon will be listed here.

Abstract

Retroviruses are RNA viruses that replicate through a DNA intermediate, in a process catalyzed by the viral reverse transcriptase (RT). Although cellular polymerases and host factors contribute to retroviral mutagenesis, the RT errors play a major role in retroviral mutation. RT mutations that affect the accuracy of the viral polymerase have been identified by in vitro analysis of the fidelity of DNA synthesis, by using enzymological (gel-based) and genetic assays (e.g., M13mp2 lacZ forward mutation assays). For several amino acid substitutions, these observations have been confirmed in cell culture using viral vectors. This review provides an update on studies leading to the identification of the major components of the fidelity center in retroviral RTs.

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References

Elder J, Lerner D, Fontenot D, Hunter E, Luciw P, Montelaro R . Distinct subsets of retroviruses encode dUTPase. J Virol. 1992; 66(3):1791-4. PMC: 240941. DOI: 10.1128/JVI.66.3.1791-1794.1992. View

Zhang W, Svarovskaia E, Barr R, Pathak V . Y586F mutation in murine leukemia virus reverse transcriptase decreases fidelity of DNA synthesis in regions associated with adenine-thymine tracts. Proc Natl Acad Sci U S A. 2002; 99(15):10090-5. PMC: 126629. DOI: 10.1073/pnas.152186199. View

Cases-Gonzalez C, Menendez-Arias L . Increased G-->A transition frequencies displayed by primer grip mutants of human immunodeficiency virus type 1 reverse transcriptase. J Virol. 2003; 78(2):1012-9. PMC: 368828. DOI: 10.1128/jvi.78.2.1012-1019.2004. View

Holmes R, Malim M, Bishop K . APOBEC-mediated viral restriction: not simply editing?. Trends Biochem Sci. 2007; 32(3):118-28. DOI: 10.1016/j.tibs.2007.01.004. View

Yu H, Goodman M . Comparison of HIV-1 and avian myeloblastosis virus reverse transcriptase fidelity on RNA and DNA templates. J Biol Chem. 1992; 267(15):10888-96. View

Abraha A, Quinones-Mateu M, Mas A, Camarasa M, Arts E . Functional characterization of chimeric reverse transcriptases with polypeptide subunits of highly divergent HIV-1 group M and O strains. J Biol Chem. 2001; 276(29):27470-9. DOI: 10.1074/jbc.M104342200. View

Chowdhury K, Kaushik N, Pandey V, Modak M . Elucidation of the role of Arg 110 of murine leukemia virus reverse transcriptase in the catalytic mechanism: biochemical characterization of its mutant enzymes. Biochemistry. 1996; 35(51):16610-20. DOI: 10.1021/bi961462l. View

Mansky L . The mutation rate of human immunodeficiency virus type 1 is influenced by the vpr gene. Virology. 1996; 222(2):391-400. DOI: 10.1006/viro.1996.0436. View

Hsu M, Inouye P, Rezende L, Richard N, Li Z, Prasad V . Higher fidelity of RNA-dependent DNA mispair extension by M184V drug-resistant than wild-type reverse transcriptase of human immunodeficiency virus type 1. Nucleic Acids Res. 1998; 25(22):4532-6. PMC: 147088. DOI: 10.1093/nar/25.22.4532. View

10.

Bakhanashvili M . p53 enhances the fidelity of DNA synthesis by human immunodeficiency virus type 1 reverse transcriptase. Oncogene. 2001; 20(52):7635-44. DOI: 10.1038/sj.onc.1204956. View

11.

Avidan O, Loya S, Tonjes R, Sevilya Z, Hizi A . Expression and characterization of a recombinant novel reverse transcriptase of a porcine endogenous retrovirus. Virology. 2003; 307(2):341-57. DOI: 10.1016/s0042-6822(02)00131-9. View

12.

Kim B, Hathaway T, Loeb L . Fidelity of mutant HIV-1 reverse transcriptases: interaction with the single-stranded template influences the accuracy of DNA synthesis. Biochemistry. 1998; 37(17):5831-9. DOI: 10.1021/bi972672g. View

13.

McWilliams M, Julias J, Sarafianos S, Alvord W, Arnold E, Hughes S . Combining mutations in HIV-1 reverse transcriptase with mutations in the HIV-1 polypurine tract affects RNase H cleavages involved in PPT utilization. Virology. 2006; 348(2):378-88. DOI: 10.1016/j.virol.2005.12.042. View

14.

Mandal D, Dash C, Le Grice S, Prasad V . Analysis of HIV-1 replication block due to substitutions at F61 residue of reverse transcriptase reveals additional defects involving the RNase H function. Nucleic Acids Res. 2006; 34(10):2853-63. PMC: 1474072. DOI: 10.1093/nar/gkl360. View

15.

Hamburgh M, Curr K, Monaghan M, Rao V, Tripathi S, Preston B . Structural determinants of slippage-mediated mutations by human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem. 2006; 281(11):7421-8. DOI: 10.1074/jbc.M511380200. View

16.

Gao G, Orlova M, Georgiadis M, Hendrickson W, Goff S . Conferring RNA polymerase activity to a DNA polymerase: a single residue in reverse transcriptase controls substrate selection. Proc Natl Acad Sci U S A. 1997; 94(2):407-11. PMC: 19524. DOI: 10.1073/pnas.94.2.407. View

17.

Kaushik N, Talele T, Pandey P, Harris D, Yadav P, Pandey V . Role of glutamine 151 of human immunodeficiency virus type-1 reverse transcriptase in substrate selection as assessed by site-directed mutagenesis. Biochemistry. 2000; 39(11):2912-20. DOI: 10.1021/bi991376w. View

18.

Balzarini J, Camarasa M, Perez-Perez M, San-Felix A, Velazquez S, Perno C . Exploitation of the low fidelity of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and the nucleotide composition bias in the HIV-1 genome to alter the drug resistance development of HIV. J Virol. 2001; 75(13):5772-7. PMC: 114293. DOI: 10.1128/JVI.75.13.5772-5777.2001. View

19.

Malim M, Emerman M . HIV-1 accessory proteins--ensuring viral survival in a hostile environment. Cell Host Microbe. 2008; 3(6):388-98. DOI: 10.1016/j.chom.2008.04.008. View

20.

Harris R, Bishop K, Sheehy A, Craig H, Petersen-Mahrt S, Watt I . DNA deamination mediates innate immunity to retroviral infection. Cell. 2003; 113(6):803-9. DOI: 10.1016/s0092-8674(03)00423-9. View