Programmed —1 Ribosomal Frameshift in the Human Immunodeficiency Virus of Type 1

  • Léa Brakier-Gingras
  • Dominic Dulude
Part of the Nucleic Acids and Molecular Biology book series (NUCLEIC, volume 24)


A programmed —1 ribosomal frameshift enables the human immunode-ficiency virus of type 1 (HIV-1) to produce its enzymes in a precise proportion relative to its structural proteins, which is necessary to control viral assembly and maturation. Here, we critically review models that account for this phenomenon, focusing on the most recent model, which postulates that the frameshift is triggered by an incomplete translocation and involves the slippage of three tRNAs. The effect of changes in the rate of translation initiation and elongation and the possible involvement of cellular factors in frameshifting are briefly examined. Finally, we highlight recent efforts intended to interfere with this type of frameshift as a strategy to develop novel anti-HIV drugs.


Simian Immunodeficiency Virus Feline Immunodeficiency Virus Infectious Bronchitis Virus Stimulatory Signal Small Ribosomal Subunit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Sergey Steinberg, Kevin Wilson and Steve Michnick for very stimulating discussions and for critical reading of this review. We are also grateful to Pascal Chartrand, Gerardo Ferbeyre, Nikolaus Heveker, Luis Rokeach and all the members of the Brakier-Gingras group for critical reading of this manuscript. Work from this laboratory that is cited herein was supported by the Canadian Institutes for Health Research.


  1. Agris PF (2008) Bringing order to translation: the contributions of transfer RNA anticodon-domain modifications. EMBO Rep 9:629–635PubMedCrossRefGoogle Scholar
  2. Baranov PV, Gesteland RF, Atkins JF (2004) P-site tRNA is a crucial initiator of ribosomal frameshifting. RNA 10:221–230PubMedCrossRefGoogle Scholar
  3. Baril M, Dulude D, Gendron K, Lemay G, Brakier-Gingras L (2003a) Efficiency of a programmed —1 ribosomal frameshift in the different subtypes of the human immunodeficiency virus type 1 group M. RNA 9:1246—1253Google Scholar
  4. Baril M, Dulude D, Steinberg SV, Brakier-Gingras L (2003b) The frameshift stimulatory signal of human immunodeficiency virus type 1 group O is a pseudoknot. J Mol Biol 331:571–583Google Scholar
  5. Biswas P, Jiang X, Pacchia AL, Dougherty JP, Peltz SW (2004) The human immunodeficiency virus type 1 ribosomal frameshifting site is an invariant sequence determinant and an important target for antiviral therapy. J Virol 78:2082–2087PubMedCrossRefGoogle Scholar
  6. Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ (2008) Identification of host proteins required for HIV infection through a functional genomic screen. Science 319:921–926PubMedCrossRefGoogle Scholar
  7. Brierley I, Dos Ramos FJ (2006) Programmed ribosomal frameshifting in HIV-1 and the SARS-CoV. Virus Res 119:29–42PubMedCrossRefGoogle Scholar
  8. Brierley I, Meredith MR, Bloys AJ, Hagervall TG (1997) Expression of a coronavirus ribosomal frameshift signal in Escherichia coli: influence of tRNA anticodon modification on frameshifting. J Mol Biol 270:360–373PubMedCrossRefGoogle Scholar
  9. Brierley I, Pennell S (2001) Structure and function of the stimulatory RNAs involved in programmed eukaryotic—1 ribosomal frameshifting. Cold Spring Harb Symp Quant Biol 66:233–248PubMedCrossRefGoogle Scholar
  10. Brierley I, Pennell S, Gilbert RJ (2007) Viral RNA pseudoknots: versatile motifs in gene expression and replication. Nature Rev Microbiol 5:598–610CrossRefGoogle Scholar
  11. Brierley I, Rolley NJ, Jenner AJ, Inglis SC (1991) Mutational analysis of the RNA pseudoknot component of a coronavirus ribosomal frameshifting signal. J Mol Biol 220:889–902PubMedCrossRefGoogle Scholar
  12. Brunelle MN, Brakier-Gingras L, Lemay G (2003) Replacement of murine leukemia virus readthrough mechanism by human immunodeficiency virus frameshift allows synthesis of viral proteins and virus replication. J Virol 77:3345–3350PubMedCrossRefGoogle Scholar
  13. Carlson BA, Kwon SY, Chamorro M, Oroszlan S, Hatfield DL, Lee BJ (1999) Transfer RNA modification status influences retroviral ribosomal frameshifting. Virology 255:2–8PubMedCrossRefGoogle Scholar
  14. Carlson BA, Mushinski JF, Henderson DW, Kwon SY, Crain PF, Lee BJ, Hatfield DL (2001) 1-Methylguanosine in place of Y base at position 37 in phenylalanine tRNA is responsible for its shiftiness in retroviral ribosomal frameshifting. Virology 279:130–135PubMedCrossRefGoogle Scholar
  15. Daviter T, Gromadski KB, Rodnina MV (2006) The ribosome’s response to codon-anticodon mismatches. Biochimie 88:1001–1011PubMedCrossRefGoogle Scholar
  16. Dinman JD, Richter S., Plant EP, Taylor RC, Hammell AB, Rana TM (2002) The frameshift signal of HIV-1 involves a potential intramolecular triplex RNA structure. Proc Natl Acad Sci USA 99:5331–5336PubMedCrossRefGoogle Scholar
  17. Dinman JD, Ruiz-Echevarria MJ, Czaplinski K., Peltz SW (1997) Peptidyl-transferase inhibitors have antiviral properties by altering programmed —1 ribosomal frameshifting efficiencies: development of model systems. Proc Natl Acad Sci USA 94:6606–6611PubMedCrossRefGoogle Scholar
  18. Dulude D, Baril M, Brakier-Gingras L (2002) Characterization of the frameshift stimulatory signal controlling a programmed –1 ribosomal frameshift in the human immunodeficiency virus type 1. Nucleic Acids Res 30:5094–5102PubMedCrossRefGoogle Scholar
  19. Dulude D, Berchiche YA, Gendron K, Brakier-Gingras L, Heveker N (2006) Decreasing the frameshift efficiency translates into an equivalent reduction of the replication of the human immunodeficiency virus type 1. Virology 345:127–136PubMedCrossRefGoogle Scholar
  20. Dulude D, Theberge-Julien G, Brakier-Gingras L, Heveker N (2008) Selection of peptides interfering with a ribosomal frameshift in the human immunodeficiency virus type 1. RNA 14:981–991PubMedCrossRefGoogle Scholar
  21. Farabaugh PJ (1997) Programmed alternative reading of the genetic code: RG Landes Company. Austin, Texas, USA and Springer-Verlag, Heidelberg, Germany, pp 69–101CrossRefGoogle Scholar
  22. Frank J, Gao H, Sengupta J, Gao N, Taylor DJ (2007) The process of mRNA-tRNA translocation. Proc Natl Acad Sci USA 104:19671–19678PubMedCrossRefGoogle Scholar
  23. Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, Cummins LB, Arthur LO, Peeters M., Shaw GM, Sharp PM, Hahn BH (1999) Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 397:436–441PubMedCrossRefGoogle Scholar
  24. Gaudin C, Mazauric MH, Traikia M, Guittet E, Yoshizawa S, Fourmy D (2005) Structure of the RNA signal essential for translational frameshifting in HIV-1. J Mol Biol 349:1024–1035PubMedCrossRefGoogle Scholar
  25. Gendron K, Charbonneau J, Dulude D, Heveker N, Ferbeyre G, Brakier-Gingras L (2008) The presence of the TAR RNA structure alters the programmed —1 ribosomal frameshift efficiency of the human immunodeficiency virus type 1 (HIV-1) by modifying the rate of translation initiation. Nucleic Acids Res 36:30–40PubMedCrossRefGoogle Scholar
  26. Gendron K, Dulude D, Lemay G, Ferbeyre G, Brakier-Gingras L (2005) The virion-associated Gag-Pol is decreased in chimeric Moloney murine leukemia viruses in which the readthrough region is replaced by the frameshift region of the human immunodeficiency virus type 1. Virology 334:342–352PubMedCrossRefGoogle Scholar
  27. Grentzmann G, Ingram JA, Kelly PJ, Gesteland RF, Atkins JF (1998) A dual-luciferase reporter system for studying recoding signals. RNA 4:479–486PubMedCrossRefGoogle Scholar
  28. Harger JW, Dinman JD (2003) An in vivo dual-luciferase assay system for studying translational recoding in the yeast Saccharomyces cerevisiae. RNA 9:1019–1024PubMedCrossRefGoogle Scholar
  29. Howard MT, Gesteland RF, Atkins JF (2004) Efficient stimulation of site-specific ribosome frameshifting by antisense oligonucleotides. RNA 10:1653–1661PubMedCrossRefGoogle Scholar
  30. Hung M, Patel P, Davis S, Green SR (1998) Importance of ribosomal frameshifting for human immunodeficiency virus type 1 particle assembly and replication. J Virol 72:4819–4824PubMedGoogle Scholar
  31. Jacks T, Madhani HD, Masiarz FR, Varmus HE (1988a) Signals for ribosomal frameshifting in the Rous sarcoma virus gag-pol region. Cell 55:447–458Google Scholar
  32. Jacks T., Power MD, Masiarz FR, Luciw PA, Barr PJ, Varmus HE (1988b) Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature 331:280–283Google Scholar
  33. Jenner L, Rees B, Yusupov M, Yusupova G (2007) Messenger RNA conformations in the ribosomal E site revealed by X-ray crystallography. EMBO Rep 8:846–850PubMedCrossRefGoogle Scholar
  34. Karacostas V, Wolffe EJ, Nagashima K, Gonda MA, Moss B (1993) Overexpression of the HIV-1 gag-pol polyprotein results in intracellular activation of HIV-1 protease and inhibition of assembly and budding of virus-like particles. Virology 193:661–671PubMedCrossRefGoogle Scholar
  35. Kollmus H, Hentze MW, Hauser H (1996) Regulated ribosomal frameshifting by an RNA-protein interaction. RNA 2:316–323PubMedGoogle Scholar
  36. Kontos H, Napthine S, Brierley I (2001) Ribosomal pausing at a frameshifter RNA pseudoknot is sensitive to reading phase but shows little correlation with frameshift efficiency. Mol Cell Biol 21:8657–8670PubMedCrossRefGoogle Scholar
  37. Léger M, Dulude D, Steinberg SV, Brakier-Gingras L (2007) The three transfer RNAs occupying the A, P and E sites on the ribosome are involved in viral programmed —1 ribosomal frameshift. Nucleic Acids Res 35:5581–5592PubMedCrossRefGoogle Scholar
  38. Léger M, Sidani S, Brakier-Gingras L (2004) A reassessment of the response of the bacterial ribosome to the frameshift stimulatory signal of the human immunodeficiency virus type 1. RNA 10:1225–1235PubMedCrossRefGoogle Scholar
  39. Liiv A, O’Connor M (2006) Mutations in the intersubunit bridge regions of 23S rRNA. J Biol Chem 281:29850–29862PubMedCrossRefGoogle Scholar
  40. Lopinski JD, Dinman JD, Bruenn JA (2000) Kinetics of ribosomal pausing during programmed —1 translational frameshifting. Mol Cell Biol 20:1095–1103PubMedCrossRefGoogle Scholar
  41. Marcheschi RJ, Staple DW, Butcher SE (2007) Programmed ribosomal frameshifting in SIV is induced by a highly structured RNA stem-loop. J Mol Biol 373:652–663PubMedCrossRefGoogle Scholar
  42. McNaughton BR, Gareiss PC, Miller BL (2007) Identification of a selective small-molecule ligand for HIV-1 frameshift-inducing stem-loop RNA from an 11,325 member resin bound dynamic combinatorial library. J Am Chem Soc 129:11306–11307PubMedCrossRefGoogle Scholar
  43. Michiels PJ, Versleijen AA, Verlaan PW, Pleij CW, Hilbers CW, Heus HA (2001) Solution structure of the pseudoknot of SRV-1 RNA, involved in ribosomal frameshifting. J Mol Biol 310:1109–1123PubMedCrossRefGoogle Scholar
  44. Moran SJ, Flanagan JF, Namy O, Stuart DI, Brierley I, Gilbert RJ (2008) The mechanics of translocation: a molecular “spring-and-ratchet” system. Structure 16:664–672PubMedCrossRefGoogle Scholar
  45. Namy O, Moran SJ, Stuart DI, Gilbert RJ, Brierley I (2006) A mechanical explanation of RNA pseudoknot function in programmed ribosomal frameshifting. Nature 441:244–247PubMedCrossRefGoogle Scholar
  46. Nierhaus KH (2006) Decoding errors and the involvement of the E-site. Biochimie 88:1013–1019PubMedCrossRefGoogle Scholar
  47. Nilsson J, Sengupta J, Frank J, Nissen P (2004) Regulation of eukaryotic translation by the RACK1 protein: a platform for signalling molecules on the ribosome. EMBO Rep 5:1137–1141PubMedCrossRefGoogle Scholar
  48. Olsthoorn RC, Laurs M, Sohet F, Hilbers CW, Heus HA, Pleij CW (2004) Novel application of sRNA: stimulation of ribosomal frameshifting. RNA 10:1702–1703PubMedCrossRefGoogle Scholar
  49. Parisien M, Major F (2008) The MC-Fold and MC-Sym pipeline infers RNA structure from sequence data. Nature 452:51–55PubMedCrossRefGoogle Scholar
  50. Park J, Morrow CD (1991) Overexpression of the gag-pol precursor from human immunodeficiency virus type 1 proviral genomes results in efficient proteolytic processing in the absence of virion production. J Virol 65:5111–5117PubMedGoogle Scholar
  51. Parkin NT, Chamorro M, Varmus HE (1992) Human immunodeficiency virus type 1 gag-pol frameshifting is dependent on downstream mRNA secondary structure: demonstration by expression in vivo. J Virol 66:5147–5151PubMedGoogle Scholar
  52. Paul CP, Barry JK, Dinesh-Kumar SP, Brault V, Miller WA (2001) A sequence required for —1 ribosomal frameshifting located four kilobases downstream of the frameshift site. J Mol Biol 310:987–999PubMedCrossRefGoogle Scholar
  53. Plant EP, Dinman JD (2006) Comparative study of the effects of heptameric slippery site composition on —1 frameshifting among different eukaryotic systems. RNA 12:666–673PubMedCrossRefGoogle Scholar
  54. Plant EP, Jacobs KL, Harger JW, Meskauskas A, Jacobs JL, Baxter JL, Petrov AN, Dinman JD (2003) The 9-A solution: how mRNA pseudoknots promote efficient programmed —1 ribosomal frameshifting. RNA 9:168–174PubMedCrossRefGoogle Scholar
  55. Rodnina MV, Gromadski KB, Kothe U, Wieden HJ (2005) Recognition and selection of tRNA in translation. FEBS Lett 579:938–942PubMedCrossRefGoogle Scholar
  56. Sanders CL, Curran JF (2007) Genetic analysis of the E site during RF2 programmed frameshifting. RNA 13:1483–1491PubMedCrossRefGoogle Scholar
  57. Sengupta J, Nilsson J, Gursky R, Spahn CM, Nissen P, Frank J (2004) Identification of the versatile scaffold protein RACK1 on the eukaryotic ribosome by cryo-EM. Nature Struct Mol Biol 11:957–962CrossRefGoogle Scholar
  58. Sharp PM, Bailes E, Chaudhuri RR, Rodenburg CM, Santiago MO, Hahn BH (2001) The origins of acquired immune deficiency syndrome viruses: where and when? Phil Trans Roy Soc (Lond.) 356:867–876CrossRefGoogle Scholar
  59. Shehu-Xhilaga M, Crowe SM, Mak J (2001) Maintenance of the Gag/Gag-Pol ratio is important for human immunodeficiency virus type 1 RNA dimerization and viral infectivity. J Virol 75:1834–1841PubMedCrossRefGoogle Scholar
  60. Shen LX, Cai Z, Tinoco I Jr (1995) RNA structure at high resolution. FASEB J 9:1023–1033PubMedGoogle Scholar
  61. Simon F, Mauclere P, Roques P, Loussert-Ajaka I, Muller-Trutwin MC, Saragosti S, Georges-Courbot MC, Barre-Sinoussi F, Brun-Vezinet F (1998) Identification of a new human immunodeficiency virus type 1 distinct from group M and group O. Nat Med 4:1032–1037PubMedCrossRefGoogle Scholar
  62. Somogyi P, Jenner AJ, Brierley I, Inglis SC (1993) Ribosomal pausing during translation of an RNA pseudoknot. Mol Cell Biol 13:6931–6940PubMedGoogle Scholar
  63. Staple DW, Butcher SE (2005) Solution structure and thermodynamic investigation of the HIV-1 frameshift inducing element. J Mol Biol 349:1011–1023PubMedCrossRefGoogle Scholar
  64. Staple DW, Venditti V, Niccolai N, Elson-Schwab L, Tor Y, Butcher SE (2008) Guanidinoneomycin B recognition of an HIV-1 RNA helix. Chembiochem 9:93–102PubMedCrossRefGoogle Scholar
  65. Su L, Chen L, Egli M, Berger JM, Rich A (1999) Minor groove RNA triplex in the crystal structure of a ribosomal frameshifting viral pseudoknot. Nature Struct Biol 6:285–292PubMedCrossRefGoogle Scholar
  66. Takyar S, Hickerson RP, Noller HF (2005) mRNA helicase activity of the ribosome. Cell 120:49–58PubMedCrossRefGoogle Scholar
  67. Telenti A, Martinez R, Munoz M, Bleiber G, Greub G, Sanglard D, Peters S (2002) Analysis of natural variants of the human immunodeficiency virus type 1 gag-pol frameshift stem-loop structure. J Virol 76:7868–7873PubMedCrossRefGoogle Scholar
  68. Tu C, Tzeng TH, Bruenn JA (1992) Ribosomal movement impeded at a pseudoknot required for frameshifting. Proc Natl Acad Sci USA 89:8636–8640PubMedCrossRefGoogle Scholar
  69. Vickers TA, Ecker DJ (1992) Enhancement of ribosomal frameshifting by oligonucleotides targeted to the HIV gag-pol region. Nucleic Acids Res 20:3945–3953PubMedCrossRefGoogle Scholar
  70. Waas WF, Druzina Z, Hanan M, Schimmel P (2007) Role of a tRNA base modification and its precursors in frameshifting in eukaryotes. J Biol Chem 282:26026–26034PubMedCrossRefGoogle Scholar
  71. Weiss RB, Dunn DM, Shuh M, Atkins JF, Gesteland RF (1989) E. coli ribosomes re-phase on retroviral frameshift signals at rates ranging from 2 to 50 percent. New Biol 1:159–169.PubMedGoogle Scholar
  72. Wen JD, Lancaster L, Hodges C, Zeri AC, Yoshimura SH, Noller HF, Bustamante C, Tinoco I (2008) Following translation by single ribosomes one codon at a time. Nature 452:598–603PubMedCrossRefGoogle Scholar
  73. Yelverton E, Lindsley D, Yamauchi P, Gallant JA (1994) The function of a ribosomal frameshifting signal from human immunodeficiency virus-1 in Escherichia coli. Mol Microbiol 11:303–313PubMedCrossRefGoogle Scholar
  74. Yu ET, Zhang Q, Fabris D (2005) Untying the FIV frameshifting pseudoknot structure by MS3D. J Mol Biol 345:69–80PubMedCrossRefGoogle Scholar
  75. Yusupov MM, Yusupova GZ, Baucom A, Lieberman K, Earnest TN, Cate JH, Noller HF (2001) Crystal structure of the ribosome at 5.5 A resolution. Science 292:883–896PubMedCrossRefGoogle Scholar
  76. Yusupova GZ, Yusupov MM, Cate JH, Noller HF (2001) The path of messenger RNA through the ribosome. Cell 106:233–241PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Département de BiochimieUniversité de MontréalMontréalCanada
  2. 2.Centre de Recherche, Hôpital Sainte-JustineMontréalCanada

Personalised recommendations