Skip to main content

Advertisement

Log in

Retroviral reverse transcriptases

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Reverse transcription is a critical step in the life cycle of all retroviruses and related retrotransposons. This complex process is performed exclusively by the retroviral reverse transcriptase (RT) enzyme that converts the viral single-stranded RNA into integration-competent double-stranded DNA. Although all RTs have similar catalytic activities, they significantly differ in several aspects of their catalytic properties, their structures and subunit composition. The RT of human immunodeficiency virus type-1 (HIV-1), the virus causing acquired immunodeficiency syndrome (AIDS), is a prime target for the development of antiretroviral drug therapy of HIV-1/AIDS carriers. Therefore, despite the fundamental contributions of other RTs to the understanding of RTs and retrovirology, most recent RT studies are related to HIV-1 RT. In this review we summarize the basic properties of different RTs. These include, among other topics, their structures, enzymatic activities, interactions with both viral and host proteins, RT inhibition and resistance to antiretroviral drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Coffin JM, Hughes SH, Varmus HE (1997) Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  2. Skalka AM, Goff SP (1993) Reverse transcriptase. Cold Spring Harbor Laboratory Press, Cold Spring Harbor

    Google Scholar 

  3. Menendez-Arias L, Berkhout B (2008) Special issue on: retroviral reverse transcription. Virus Res 134

  4. Parniak MA (2004) Special issue: molecular biology of HIV. Int J Biochem Cell Biol 36

  5. Katz RA, Skalka AM (1994) The retroviral enzymes. Annu Rev Biochem 63:133–173

    Article  PubMed  CAS  Google Scholar 

  6. Sarafianos SG, Marchand B, Das K, Himmel DM, Parniak MA, Hughes SH, Arnold E (2009) Structure and function of HIV-1 reverse transcriptase: molecular mechanisms of polymerization and inhibition. J Mol Biol 385:693–713

    Article  PubMed  CAS  Google Scholar 

  7. Hizi A, Herschhorn A (2008) Retroviral reverse transcriptases (other than those of HIV-1 and murine leukemia virus): a comparison of their molecular and biochemical properties. Virus Res 134:203–220

    Article  PubMed  CAS  Google Scholar 

  8. Linial M (2007) Foamy viruses. In: Knife DM, Howley PM (eds) Fields virology, vol 2. Lippincott Williams & Williams, Philadelphia, pp 2245–2262

    Google Scholar 

  9. Nassal M (2008) Hepatitis B viruses: reverse transcription a different way. Virus Res 134:235–249

    Article  PubMed  CAS  Google Scholar 

  10. Hizi A, Joklik WK (1977) RNA-dependent DNA polymerase of avian sarcoma virus B77. I. Isolation and partial characterization of the alpha, beta2, and alphabeta forms of the enzyme. J Biol Chem 252:2281–2289

    PubMed  CAS  Google Scholar 

  11. Sluis-Cremer N, Arion D, Abram ME, Parniak MA (2004) Proteolytic processing of an HIV-1 pol polyprotein precursor: insights into the mechanism of reverse transcriptase p66/p51 heterodimer formation. Int J Biochem Cell Biol 36:1836–1847

    Article  PubMed  CAS  Google Scholar 

  12. Hizi A, Leis JP, Joklik WK (1977) RNA-dependent DNA polymerase of avian sarcoma virus B77. II. Comparison of the catalytic properties of the alpha, beta2, and alphabeta enzyme forms. J Biol Chem 252:2290–2295

    PubMed  CAS  Google Scholar 

  13. Hizi A, Leis JP, Joklik WK (1977) The RNA-dependent DNA polymerase of avian sarcoma virus B77. Binding of viral and nonviral ribonucleic acids to the alpha, beta2, and alphabeta forms of the enzyme. J Biol Chem 252:6878–6884

    PubMed  CAS  Google Scholar 

  14. Restle T, Muller B, Goody RS (1990) Dimerization of human immunodeficiency virus type 1 reverse transcriptase. A target for chemotherapeutic intervention. J Biol Chem 265:8986–8988

    PubMed  CAS  Google Scholar 

  15. Wohrl BM, Howard KJ, Jacques PS, Le Grice SF (1994) Alternative modes of polymerization distinguish the subunits of equine infectious anemia virus reverse transcriptase. J Biol Chem 269:8541–8548

    PubMed  CAS  Google Scholar 

  16. Hizi A, McGill C, Hughes SH (1988) Expression of soluble, enzymatically active, human immunodeficiency virus reverse transcriptase in Escherichia coli and analysis of mutants. Proc Natl Acad Sci USA 85:1218–1222

    Article  PubMed  CAS  Google Scholar 

  17. Taube R, Loya S, Avidan O, Perach M, Hizi A (1998) Reverse transcriptase of mouse mammary tumour virus: expression in bacteria, purification and biochemical characterization. Biochem J 329(Pt 3):579–587

    PubMed  CAS  Google Scholar 

  18. Entin-Meer M, Avidan O, Hizi A (2003) The mature reverse transcriptase molecules in virions of mouse mammary tumor virus possess protease-derived sequences. Virology 310:157–162

    Article  PubMed  CAS  Google Scholar 

  19. Perach M, Hizi A (1999) Catalytic features of the recombinant reverse transcriptase of bovine leukemia virus expressed in bacteria. Virology 259:176–189

    Article  PubMed  CAS  Google Scholar 

  20. Le Grice SF (2003) “In the beginning”: initiation of minus strand DNA synthesis in retroviruses and LTR-containing retrotransposons. Biochemistry 42:14349–14355

    Article  PubMed  CAS  Google Scholar 

  21. Abbink TE, Berkhout B (2008) HIV-1 reverse transcription initiation: a potential target for novel antivirals? Virus Res 134:4–18

    Article  PubMed  CAS  Google Scholar 

  22. Levin HL (1997) It’s prime time for reverse transcriptase. Cell 88:5–8

    Article  PubMed  CAS  Google Scholar 

  23. Hizi A (2008) The reverse transcriptase of the Tf1 retrotransposon has a specific novel activity for generating the RNA self-primer that is functional in cDNA synthesis. J Virol 82:10906–10910

    Article  PubMed  CAS  Google Scholar 

  24. Schultz SJ, Champoux JJ (2008) RNase H activity: structure, specificity, and function in reverse transcription. Virus Res 134:86–103

    Article  PubMed  CAS  Google Scholar 

  25. Champoux JJ, Schultz SJ (2009) Ribonuclease H: properties, substrate specificity and roles in retroviral reverse transcription. FEBS J 276:1506–1516

    Article  PubMed  CAS  Google Scholar 

  26. Yu H, Jetzt AE, Ron Y, Preston BD, Dougherty JP (1998) The nature of human immunodeficiency virus type 1 strand transfers. J Biol Chem 273:28384–28391

    Article  PubMed  CAS  Google Scholar 

  27. van Wamel JL, Berkhout B (1998) The first strand transfer during HIV-1 reverse transcription can occur either intramolecularly or intermolecularly. Virology 244:245–251

    Article  PubMed  Google Scholar 

  28. Rausch JW, Le Grice SF (2004) ‘Binding, bending and bonding’: polypurine tract-primed initiation of plus-strand DNA synthesis in human immunodeficiency virus. Int J Biochem Cell Biol 36:1752–1766

    Article  PubMed  CAS  Google Scholar 

  29. Charneau P, Alizon M, Clavel F (1992) A second origin of DNA plus-strand synthesis is required for optimal human immunodeficiency virus replication. J Virol 66:2814–2820

    PubMed  CAS  Google Scholar 

  30. Hameau L, Jeusset J, Lafosse S, Coulaud D, Delain E, Unge T, Restle T, Le Cam E, Mirambeau G (2001) Human immunodeficiency virus type 1 central DNA flap: dynamic terminal product of plus-strand displacement dna synthesis catalyzed by reverse transcriptase assisted by nucleocapsid protein. J Virol 75:3301–3313

    Article  PubMed  CAS  Google Scholar 

  31. Zennou V, Petit C, Guetard D, Nerhbass U, Montagnier L, Charneau P (2000) HIV-1 genome nuclear import is mediated by a central DNA flap. Cell 101:173–185

    Article  PubMed  CAS  Google Scholar 

  32. Arhel NJ, Souquere-Besse S, Munier S, Souque P, Guadagnini S, Rutherford S, Prevost MC, Allen TD, Charneau P (2007) HIV-1 DNA Flap formation promotes uncoating of the pre-integration complex at the nuclear pore. EMBO J 26:3025–3037

    Article  PubMed  CAS  Google Scholar 

  33. Limon A, Nakajima N, Lu R, Ghory HZ, Engelman A (2002) Wild-type levels of nuclear localization and human immunodeficiency virus type 1 replication in the absence of the central DNA flap. J Virol 76:12078–12086

    Article  PubMed  CAS  Google Scholar 

  34. Marsden MD, Zack JA (2007) Human immunodeficiency virus bearing a disrupted central DNA flap is pathogenic in vivo. J Virol 81:6146–6150

    Article  PubMed  CAS  Google Scholar 

  35. Dvorin JD, Bell P, Maul GG, Yamashita M, Emerman M, Malim MH (2002) Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type 1 nuclear import. J Virol 76:12087–12096

    Article  PubMed  CAS  Google Scholar 

  36. Basu VP, Song M, Gao L, Rigby ST, Hanson MN, Bambara RA (2008) Strand transfer events during HIV-1 reverse transcription. Virus Res 134:19–38

    Article  PubMed  CAS  Google Scholar 

  37. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256:1783–1790

    Article  PubMed  CAS  Google Scholar 

  38. Jacobo-Molina A, Ding J, Nanni RG, Clark AD Jr, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clark P, Hizi A, Hughes SH, Arnold E (1993) Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA. Proc Natl Acad Sci USA 90:6320–6324

    Article  PubMed  CAS  Google Scholar 

  39. Sevilya Z, Loya S, Hughes SH, Hizi A (2001) The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is affected by the thumb subdomain of the small protein subunits. J Mol Biol 311:957–971

    Article  PubMed  CAS  Google Scholar 

  40. Sevilya Z, Loya S, Adir N, Hizi A (2003) The ribonuclease H activity of the reverse transcriptases of human immunodeficiency viruses type 1 and type 2 is modulated by residue 294 of the small subunit. Nucleic Acids Res 31:1481–1487

    Article  PubMed  CAS  Google Scholar 

  41. Sarafianos SG, Das K, Tantillo C, Clark AD Jr, Ding J, Whitcomb JM, Boyer PL, Hughes SH, Arnold E (2001) Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA. EMBO J 20:1449–1461

    Article  PubMed  CAS  Google Scholar 

  42. Huang H, Chopra R, Verdine GL, Harrison SC (1998) Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science 282:1669–1675

    Article  PubMed  CAS  Google Scholar 

  43. Hsiou Y, Ding J, Das K, Clark AD Jr, Hughes SH, Arnold E (1996) Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms. Structure 4:853–860

    Article  PubMed  CAS  Google Scholar 

  44. Rodgers DW, Gamblin SJ, Harris BA, Ray S, Culp JS, Hellmig B, Woolf DJ, Debouck C, Harrison SC (1995) The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1. Proc Natl Acad Sci USA 92:1222–1226

    Article  PubMed  CAS  Google Scholar 

  45. Esnouf R, Ren J, Ross C, Jones Y, Stammers D, Stuart D (1995) Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat Struct Biol 2:303–308

    Article  PubMed  CAS  Google Scholar 

  46. Sarafianos SG, Clark AD Jr, Das K, Tuske S, Birktoft JJ, Ilankumaran P, Ramesha AR, Sayer JM, Jerina DM, Boyer PL, Hughes SH, Arnold E (2002) Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J 21:6614–6624

    Article  PubMed  CAS  Google Scholar 

  47. Marchand B, Tchesnokov EP, Gotte M (2007) The pyrophosphate analogue foscarnet traps the pre-translocational state of HIV-1 reverse transcriptase in a Brownian ratchet model of polymerase translocation. J Biol Chem 282:3337–3346

    Article  PubMed  CAS  Google Scholar 

  48. Gotte M, Rausch JW, Marchand B, Sarafianos S, Le Grice SF (2009) Reverse transcriptase in motion: Conformational dynamics of enzyme-substrate interactions. Biochim Biophys Acta. doi:10.1016/j.bbapap.2009.07.020

  49. Kew Y, Olsen LR, Japour AJ, Prasad VR (1998) Insertions into the beta3–beta4 hairpin loop of HIV-1 reverse transcriptase reveal a role for fingers subdomain in processive polymerization. J Biol Chem 273:7529–7537

    Article  PubMed  CAS  Google Scholar 

  50. Kim B, Ayran JC, Sagar SG, Adman ET, Fuller SM, Tran NH, Horrigan J (1999) New human immunodeficiency virus, type 1 reverse transcriptase (HIV-1 RT) mutants with increased fidelity of DNA synthesis. Accuracy, template binding, and processivity. J Biol Chem 274:27666–27673

    Article  PubMed  CAS  Google Scholar 

  51. Fisher TS, Darden T, Prasad VR (2003) Substitutions at Phe61 in the beta3-beta4 hairpin of HIV-1 reverse transcriptase reveal a role for the Fingers subdomain in strand displacement DNA synthesis. J Mol Biol 325:443–459

    Article  PubMed  CAS  Google Scholar 

  52. Boyer PL, Sarafianos SG, Arnold E, Hughes SH (2000) Analysis of mutations at positions 115 and 116 in the dNTP binding site of HIV-1 reverse transcriptase. Proc Natl Acad Sci USA 97:3056–3061

    Article  PubMed  CAS  Google Scholar 

  53. Gao G, Orlova M, Georgiadis MM, Hendrickson WA, Goff SP (1997) Conferring RNA polymerase activity to a DNA polymerase: a single residue in reverse transcriptase controls substrate selection. Proc Natl Acad Sci USA 94:407–411

    Article  PubMed  CAS  Google Scholar 

  54. Martin-Hernandez AM, Domingo E, Menendez-Arias L (1996) Human immunodeficiency virus type 1 reverse transcriptase: role of Tyr115 in deoxynucleotide binding and misinsertion fidelity of DNA synthesis. EMBO J 15:4434–4442

    PubMed  CAS  Google Scholar 

  55. Nowotny M, Gaidamakov SA, Crouch RJ, Yang W (2005) Crystal structures of RNase H bound to an RNA/DNA hybrid: substrate specificity and metal-dependent catalysis. Cell 121:1005–1016

    Article  PubMed  CAS  Google Scholar 

  56. Davies JF 2nd, Hostomska Z, Hostomsky Z, Jordan SR, Matthews DA (1991) Crystal structure of the ribonuclease H domain of HIV-1 reverse transcriptase. Science 252:88–95

    Article  PubMed  CAS  Google Scholar 

  57. Evans DB, Brawn K, Deibel MR Jr, Tarpley WG, Sharma SK (1991) A recombinant ribonuclease H domain of HIV-1 reverse transcriptase that is enzymatically active. J Biol Chem 266:20583–20585

    PubMed  CAS  Google Scholar 

  58. Smith JS, Roth MJ (1993) Purification and characterization of an active human immunodeficiency virus type 1 RNase H domain. J Virol 67:4037–4049

    PubMed  CAS  Google Scholar 

  59. Keck JL, Marqusee S (1995) Substitution of a highly basic helix/loop sequence into the RNase H domain of human immunodeficiency virus reverse transcriptase restores its Mn(2+)-dependent RNase H activity. Proc Natl Acad Sci USA 92:2740–2744

    Article  PubMed  CAS  Google Scholar 

  60. Stahl SJ, Kaufman JD, Vikic-Topic S, Crouch RJ, Wingfield PT (1994) Construction of an enzymatically active ribonuclease H domain of human immunodeficiency virus type 1 reverse transcriptase. Protein Eng 7:1103–1108

    Article  PubMed  CAS  Google Scholar 

  61. Hostomsky Z, Hostomska Z, Hudson GO, Moomaw EW, Nodes BR (1991) Reconstitution in vitro of RNase H activity by using purified N-terminal and C-terminal domains of human immunodeficiency virus type 1 reverse transcriptase. Proc Natl Acad Sci USA 88:1148–1152

    Article  PubMed  CAS  Google Scholar 

  62. Smith JS, Gritsman K, Roth MJ (1994) Contributions of DNA polymerase subdomains to the RNase H activity of human immunodeficiency virus type 1 reverse transcriptase. J Virol 68:5721–5729

    PubMed  CAS  Google Scholar 

  63. North TW, Cronn RC, Remington KM, Tandberg RT, Judd RC (1990) Characterization of reverse transcriptase from feline immunodeficiency virus. J Biol Chem 265:5121–5128

    PubMed  CAS  Google Scholar 

  64. Amacker M, Hottiger M, Hubscher U (1995) Feline immunodeficiency virus reverse transcriptase: expression, functional characterization, and reconstitution of the 66- and 51-kilodalton subunits. J Virol 69:6273–6279

    PubMed  CAS  Google Scholar 

  65. Avidan O, Bochner R, Hizi A (2006) The catalytic properties of the recombinant reverse transcriptase of bovine immunodeficiency virus. Virology 351:42–57

    Article  PubMed  CAS  Google Scholar 

  66. Souquet M, Restle T, Krebs R, Le Grice SF, Goody RS, Wohrl BM (1998) Analysis of the polymerization kinetics of homodimeric EIAV p51/51 reverse transcriptase implies the formation of a polymerase active site identical to heterodimeric EIAV p66/51 reverse transcriptase. Biochemistry 37:12144–12152

    Article  PubMed  CAS  Google Scholar 

  67. Shaharabany M, Rice NR, Hizi A (1993) Expression and mutational analysis of the reverse transcriptase of the lentivirus equine infectious anemia virus. Biochem Biophys Res Commun 196:914–920

    Article  PubMed  CAS  Google Scholar 

  68. Shaharabany M, Hizi A (1992) The catalytic functions of chimeric reverse transcriptases of human immunodeficiency viruses type 1 and type 2. J Biol Chem 267:3674–3678

    PubMed  CAS  Google Scholar 

  69. Fan N, Rank KB, Leone JW, Heinrikson RL, Bannow CA, Smith CW, Evans DB, Poppe SM, Tarpley WG, Rothrock DJ, Tomassseli AG, Sharma SK (1995) The differential processing of homodimers of reverse transcriptases from human immunodeficiency viruses type 1 and 2 is a consequence of the distinct specificities of the viral proteases. J Biol Chem 270:13573–13579

    PubMed  CAS  Google Scholar 

  70. Bird LE, Chamberlain PP, Stewart-Jones GB, Ren J, Stuart DI, Stammers DK (2003) Cloning, expression, purification, and crystallisation of HIV-2 reverse transcriptase. Protein Expr Purif 27:12–18

    Article  PubMed  CAS  Google Scholar 

  71. Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK (2002) Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors. Proc Natl Acad Sci USA 99:14410–14415

    Article  PubMed  CAS  Google Scholar 

  72. Divita G, Rittinger K, Restle T, Immendorfer U, Goody RS (1995) Conformational stability of dimeric HIV-1 and HIV-2 reverse transcriptases. Biochemistry 34:16337–16346

    Article  PubMed  CAS  Google Scholar 

  73. Das D, Georgiadis MM (2004) The crystal structure of the monomeric reverse transcriptase from Moloney murine leukemia virus. Structure 12:819–829

    Article  PubMed  CAS  Google Scholar 

  74. Lim D, Gregorio GG, Bingman C, Martinez-Hackert E, Hendrickson WA, Goff SP (2006) Crystal structure of the moloney murine leukemia virus RNase H domain. J Virol 80:8379–8389

    Article  PubMed  CAS  Google Scholar 

  75. Cote ML, Roth MJ (2008) Murine leukemia virus reverse transcriptase: structural comparison with HIV-1 reverse transcriptase. Virus Res 134:186–202

    Article  PubMed  CAS  Google Scholar 

  76. Shindyalov IN, Bourne PE (1998) Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. Protein Eng 11:739–747

    Article  PubMed  CAS  Google Scholar 

  77. Hizi A, Joklik WK (1977) The beta subunit of the DNA polymerase of avian sarcoma virus strain B77 is a phosphoprotein. Virology 78:571–575

    Article  PubMed  CAS  Google Scholar 

  78. Hizi A (1982) Regulation of Rous sarcoma virus RNA-dependent DNA polymerase isoenzymes by in vitro phosphorylation-dephosphorylation. Arch Biochem Biophys 219:394–400

    Article  PubMed  CAS  Google Scholar 

  79. Rezende LF, Prasad VR (2004) Nucleoside-analog resistance mutations in HIV-1 reverse transcriptase and their influence on polymerase fidelity and viral mutation rates. Int J Biochem Cell Biol 36:1716–1734

    Article  PubMed  CAS  Google Scholar 

  80. Kati WM, Johnson KA, Jerva LF, Anderson KS (1992) Mechanism and fidelity of HIV reverse transcriptase. J Biol Chem 267:25988–25997

    PubMed  CAS  Google Scholar 

  81. Rittinger K, Divita G, Goody RS (1995) Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc Natl Acad Sci USA 92:8046–8049

    Article  PubMed  CAS  Google Scholar 

  82. Cases-Gonzalez CE, Gutierrez-Rivas M, Menendez-Arias L (2000) Coupling ribose selection to fidelity of DNA synthesis. The role of Tyr-115 of human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem 275:19759–19767

    Article  PubMed  CAS  Google Scholar 

  83. Entin-Meer M, Sevilya Z, Hizi A (2002) The role of phenylalanine-119 of the reverse transcriptase of mouse mammary tumour virus in DNA synthesis, ribose selection and drug resistance. Biochem J 367:381–391

    Article  PubMed  CAS  Google Scholar 

  84. Patel PH, Preston BD (1994) Marked infidelity of human immunodeficiency virus type 1 reverse transcriptase at RNA and DNA template ends. Proc Natl Acad Sci USA 91:549–553

    Article  PubMed  CAS  Google Scholar 

  85. Golinelli MP, Hughes SH (2002) Nontemplated base addition by HIV-1 RT can induce nonspecific strand transfer in vitro. Virology 294:122–134

    Article  PubMed  CAS  Google Scholar 

  86. Kirshenboim N, Hayouka Z, Friedler A, Hizi A (2007) Expression and characterization of a novel reverse transcriptase of the LTR retrotransposon Tf1. Virology 366:263–276

    Article  PubMed  CAS  Google Scholar 

  87. Atwood-Moore A, Ejebe K, Levin HL (2005) Specific recognition and cleavage of the plus-strand primer by reverse transcriptase. J Virol 79:14863–14875

    Article  PubMed  CAS  Google Scholar 

  88. Avidan O, Meer ME, Oz I, Hizi A (2002) The processivity and fidelity of DNA synthesis exhibited by the reverse transcriptase of bovine leukemia virus. Eur J Biochem 269:859–867

    Article  PubMed  CAS  Google Scholar 

  89. Avidan O, Hizi A (1998) The processivity of DNA synthesis exhibited by drug-resistant variants of human immunodeficiency virus type-1 reverse transcriptase. Nucleic Acids Res 26:1713–1717

    Article  PubMed  CAS  Google Scholar 

  90. Oude Essink BB, Back NK, Berkhout B (1997) Increased polymerase fidelity of the 3TC-resistant variants of HIV-1 reverse transcriptase. Nucleic Acids Res 25:3212–3217

    Article  PubMed  CAS  Google Scholar 

  91. Bakhanashvili M, Avidan O, Hizi A (1996) Mutational studies of human immunodeficiency virus type 1 reverse transcriptase: the involvement of residues 183 and 184 in the fidelity of DNA synthesis. FEBS Lett 391:257–262

    Article  PubMed  CAS  Google Scholar 

  92. Wainberg MA, Drosopoulos WC, Salomon H, Hsu M, Borkow G, Parniak M, Gu Z, Song Q, Manne J, Islam S, Castriota G, Prasad VR (1996) Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 271:1282–1285

    Article  PubMed  CAS  Google Scholar 

  93. Rubinek T, Bakhanashvili M, Taube R, Avidan O, Hizi A (1997) The fidelity of 3′ misinsertion and mispair extension during DNA synthesis exhibited by two drug-resistant mutants of the reverse transcriptase of human immunodeficiency virus type 1 with Leu74 → Val and Glu89 → Gly. Eur J Biochem 247:238–247

    Article  PubMed  CAS  Google Scholar 

  94. Pandey VN, Kaushik N, Rege N, Sarafianos SG, Yadav PN, Modak MJ (1996) Role of methionine 184 of human immunodeficiency virus type-1 reverse transcriptase in the polymerase function and fidelity of DNA synthesis. Biochemistry 35:2168–2179

    Article  PubMed  CAS  Google Scholar 

  95. Bebenek K, Kunkel TA (1993) The fidelity of retroviral reverse transcriptases. In: Sakaka AM, Goff SP (eds) Reverse transcriptase. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, pp 85–102

    Google Scholar 

  96. Menendez-Arias L (2009) Mutation rates and intrinsic fidelity of retroviral reverse transcriptases. Viruses 1:1137–1165

    Article  CAS  Google Scholar 

  97. Yu H, Goodman MF (1992) Comparison of HIV-1 and avian myeloblastosis virus reverse transcriptase fidelity on RNA and DNA templates. J Biol Chem 267:10888–10896

    PubMed  CAS  Google Scholar 

  98. Bakhanashvili M, Hizi A (1992) Fidelity of the RNA-dependent DNA synthesis exhibited by the reverse transcriptases of human immunodeficiency virus types 1 and 2 and of murine leukemia virus: mispair extension frequencies. Biochemistry 31:9393–9398

    Article  PubMed  CAS  Google Scholar 

  99. Bakhanashvili M, Hizi A (1993) The fidelity of the reverse transcriptases of human immunodeficiency viruses and murine leukemia virus, exhibited by the mispair extension frequencies, is sequence dependent and enzyme related. FEBS Lett 319:201–205

    Article  PubMed  CAS  Google Scholar 

  100. Bakhanashvili M, Hizi A (1993) Fidelity of DNA synthesis exhibited in vitro by the reverse transcriptase of the lentivirus equine infectious anemia virus. Biochemistry 32:7559–7567

    Article  PubMed  CAS  Google Scholar 

  101. Menendez-Arias L (2002) Molecular basis of fidelity of DNA synthesis and nucleotide specificity of retroviral reverse transcriptases. Prog Nucleic Acid Res Mol Biol 71:91–147

    Article  PubMed  CAS  Google Scholar 

  102. Mansky LM, Preveral S, Selig L, Benarous R, Benichou S (2000) The interaction of vpr with uracil DNA glycosylase modulates the human immunodeficiency virus type 1 in vivo mutation rate. J Virol 74:7039–7047

    Article  PubMed  CAS  Google Scholar 

  103. Aguiar RS, Peterlin BM (2008) APOBEC3 proteins and reverse transcription. Virus Res 134:74–85

    Article  PubMed  CAS  Google Scholar 

  104. Levin JG, Guo J, Rouzina I, Musier-Forsyth K (2005) Nucleic acid chaperone activity of HIV-1 nucleocapsid protein: critical role in reverse transcription and molecular mechanism. Prog Nucleic Acid Res Mol Biol 80:217–286

    Article  PubMed  Google Scholar 

  105. Bampi C, Bibillo A, Wendeler M, Divita G, Gorelick RJ, Le Grice SF, Darlix JL (2006) Nucleotide excision repair and template-independent addition by HIV-1 reverse transcriptase in the presence of nucleocapsid protein. J Biol Chem 281:11736–11743

    Article  PubMed  CAS  Google Scholar 

  106. Thomas JA, Gorelick RJ (2008) Nucleocapsid protein function in early infection processes. Virus Res 134:39–63

    Article  PubMed  CAS  Google Scholar 

  107. Hwang CK, Svarovskaia ES, Pathak VK (2001) Dynamic copy choice: steady state between murine leukemia virus polymerase and polymerase-dependent RNase H activity determines frequency of in vivo template switching. Proc Natl Acad Sci USA 98:12209–12214

    Article  PubMed  CAS  Google Scholar 

  108. Kelleher CD, Champoux JJ (1998) Characterization of RNA strand displacement synthesis by Moloney murine leukemia virus reverse transcriptase. J Biol Chem 273:9976–9986

    Article  PubMed  CAS  Google Scholar 

  109. Whiting SH, Champoux JJ (1998) Properties of strand displacement synthesis by Moloney murine leukemia virus reverse transcriptase: mechanistic implications. J Mol Biol 278:559–577

    Article  PubMed  CAS  Google Scholar 

  110. Boone LR, Skalka AM (1981) Viral DNA synthesized in vitro by avian retrovirus particles permeabilized with melittin. I. Kinetics of synthesis and size of minus- and plus-strand transcripts. J Virol 37:109–116

    PubMed  CAS  Google Scholar 

  111. Fuentes GM, Rodriguez-Rodriguez L, Palaniappan C, Fay PJ, Bambara RA (1996) Strand displacement synthesis of the long terminal repeats by HIV reverse transcriptase. J Biol Chem 271:1966–1971

    Article  PubMed  CAS  Google Scholar 

  112. Winshell J, Paulson BA, Buelow BD, Champoux JJ (2004) Requirements for DNA unpairing during displacement synthesis by HIV-1 reverse transcriptase. J Biol Chem 279:52924–52933

    Article  PubMed  CAS  Google Scholar 

  113. Nowotny M, Gaidamakov SA, Ghirlando R, Cerritelli SM, Crouch RJ, Yang W (2007) Structure of human RNase H1 complexed with an RNA/DNA hybrid: insight into HIV reverse transcription. Mol Cell 28:264–276

    Article  PubMed  CAS  Google Scholar 

  114. Wohrl BM, Georgiadis MM, Telesnitsky A, Hendrickson WA, Le Grice SF (1995) Footprint analysis of replicating murine leukemia virus reverse transcriptase. Science 267:96–99

    Article  PubMed  CAS  Google Scholar 

  115. Wohrl BM, Tantillo C, Arnold E, Le Grice SF (1995) An expanded model of replicating human immunodeficiency virus reverse transcriptase. Biochemistry 34:5343–5356

    Article  PubMed  CAS  Google Scholar 

  116. Schultz SJ, Champoux JJ (1996) RNase H domain of Moloney murine leukemia virus reverse transcriptase retains activity but requires the polymerase domain for specificity. J Virol 70:8630–8638

    PubMed  CAS  Google Scholar 

  117. Mandal D, Dash C, Le Grice SF, Prasad VR (2006) 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 34:2853–2863

    Article  PubMed  CAS  Google Scholar 

  118. Powell MD, Beard WA, Bebenek K, Howard KJ, Le Grice SF, Darden TA, Kunkel TA, Wilson SH, Levin JG (1999) Residues in the alphaH and alphaI helices of the HIV-1 reverse transcriptase thumb subdomain required for the specificity of RNase H-catalyzed removal of the polypurine tract primer. J Biol Chem 274:19885–19893

    Article  PubMed  CAS  Google Scholar 

  119. Julias JG, McWilliams MJ, Sarafianos SG, Arnold E, Hughes SH (2002) Mutations in the RNase H domain of HIV-1 reverse transcriptase affect the initiation of DNA synthesis and the specificity of RNase H cleavage in vivo. Proc Natl Acad Sci USA 99:9515–9520

    Article  PubMed  CAS  Google Scholar 

  120. Bochner R, Duvshani A, Adir N, Hizi A (2008) Mutagenesis of Gln294 of the reverse transcriptase of human immunodeficiency virus type-2 and its effects on the ribonuclease H activity. FEBS Lett 582:2799–2805

    Article  PubMed  CAS  Google Scholar 

  121. Hizi A, Tal R, Hughes SH (1991) Mutational analysis of the DNA polymerase and ribonuclease H activities of human immunodeficiency virus type 2 reverse transcriptase expressed in Escherichia coli. Virology 180:339–346

    Article  PubMed  CAS  Google Scholar 

  122. Telesnitsky A, Goff SP (1993) RNase H domain mutations affect the interaction between Moloney murine leukemia virus reverse transcriptase and its primer-template. Proc Natl Acad Sci USA 90:1276–1280

    Article  PubMed  CAS  Google Scholar 

  123. Brehm JH, Koontz D, Meteer JD, Pathak V, Sluis-Cremer N, Mellors JW (2007) Selection of mutations in the connection and RNase H domains of human immunodeficiency virus type 1 reverse transcriptase that increase resistance to 3′-azido-3′-dideoxythymidine. J Virol 81:7852–7859

    Article  PubMed  CAS  Google Scholar 

  124. Gotte M (2007) Should we include connection domain mutations of HIV-1 reverse transcriptase in HIV resistance testing. PLoS Med 4:e346

    Article  PubMed  Google Scholar 

  125. Nikolenko GN, Svarovskaia ES, Delviks KA, Pathak VK (2004) Antiretroviral drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase increase template-switching frequency. J Virol 78:8761–8770

    Article  PubMed  CAS  Google Scholar 

  126. Svarovskaia ES, Delviks KA, Hwang CK, Pathak VK (2000) Structural determinants of murine leukemia virus reverse transcriptase that affect the frequency of template switching. J Virol 74:7171–7178

    Article  PubMed  CAS  Google Scholar 

  127. Menendez-Arias L (2008) Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res 134:124–146

    Article  PubMed  CAS  Google Scholar 

  128. Nikolenko GN, Palmer S, Maldarelli F, Mellors JW, Coffin JM, Pathak VK (2005) Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: balance between RNase H activity and nucleotide excision. Proc Natl Acad Sci USA 102:2093–2098

    Article  PubMed  CAS  Google Scholar 

  129. Delviks-Frankenberry KA, Nikolenko GN, Barr R, Pathak VK (2007) Mutations in human immunodeficiency virus type 1 RNase H primer grip enhance 3′-azido-3′-deoxythymidine resistance. J Virol 81:6837–6845

    Article  PubMed  CAS  Google Scholar 

  130. Delviks-Frankenberry KA, Nikolenko GN, Boyer PL, Hughes SH, Coffin JM, Jere A, Pathak VK (2008) HIV-1 reverse transcriptase connection subdomain mutations reduce template RNA degradation and enhance AZT excision. Proc Natl Acad Sci USA 105:10943–10948

    Article  PubMed  Google Scholar 

  131. Abbondanzieri EA, Bokinsky G, Rausch JW, Zhang JX, Le Grice SF, Zhuang X (2008) Dynamic binding orientations direct activity of HIV reverse transcriptase. Nature 453:184–189

    Article  PubMed  CAS  Google Scholar 

  132. Liu S, Abbondanzieri EA, Rausch JW, Le Grice SF, Zhuang X (2008) Slide into action: dynamic shuttling of HIV reverse transcriptase on nucleic acid substrates. Science 322:1092–1097

    Article  PubMed  CAS  Google Scholar 

  133. DeStefano JJ, Mallaber LM, Fay PJ, Bambara RA (1993) Determinants of the RNase H cleavage specificity of human immunodeficiency virus reverse transcriptase. Nucleic Acids Res 21:4330–4338

    Article  PubMed  CAS  Google Scholar 

  134. Palaniappan C, Fuentes GM, Rodriguez-Rodriguez L, Fay PJ, Bambara RA (1996) Helix structure and ends of RNA/DNA hybrids direct the cleavage specificity of HIV-1 reverse transcriptase RNase H. J Biol Chem 271:2063–2070

    Article  PubMed  CAS  Google Scholar 

  135. Grobler JA, Dornadula G, Rice MR, Simcoe AL, Hazuda DJ, Miller MD (2007) HIV-1 reverse transcriptase plus-strand initiation exhibits preferential sensitivity to non-nucleoside reverse transcriptase inhibitors in vitro. J Biol Chem 282:8005–8010

    Article  PubMed  CAS  Google Scholar 

  136. Nymark-McMahon MH, Beliakova-Bethell NS, Darlix JL, Le Grice SF, Sandmeyer SB (2002) Ty3 integrase is required for initiation of reverse transcription. J Virol 76:2804–2816

    Article  PubMed  CAS  Google Scholar 

  137. Mougel M, Houzet L, Darlix JL (2009) When is it time for reverse transcription to start and go? Retrovirology 6:24

    Article  PubMed  CAS  Google Scholar 

  138. Peliska JA, Balasubramanian S, Giedroc DP, Benkovic SJ (1994) Recombinant HIV-1 nucleocapsid protein accelerates HIV-1 reverse transcriptase catalyzed DNA strand transfer reactions and modulates RNase H activity. Biochemistry 33:13817–13823

    Article  PubMed  CAS  Google Scholar 

  139. Guo J, Wu T, Anderson J, Kane BF, Johnson DG, Gorelick RJ, Henderson LE, Levin JG (2000) Zinc finger structures in the human immunodeficiency virus type 1 nucleocapsid protein facilitate efficient minus- and plus-strand transfer. J Virol 74:8980–8988

    Article  PubMed  CAS  Google Scholar 

  140. Roda RH, Balakrishnan M, Hanson MN, Wohrl BM, Le Grice SF, Roques BP, Gorelick RJ, Bambara RA (2003) Role of the reverse transcriptase, nucleocapsid protein, and template structure in the two-step transfer mechanism in retroviral recombination. J Biol Chem 278:31536–31546

    Article  PubMed  CAS  Google Scholar 

  141. Johnson PE, Turner RB, Wu ZR, Hairston L, Guo J, Levin JG, Summers MF (2000) A mechanism for plus-strand transfer enhancement by the HIV-1 nucleocapsid protein during reverse transcription. Biochemistry 39:9084–9091

    Article  PubMed  CAS  Google Scholar 

  142. Post K, Kankia B, Gopalakrishnan S, Yang V, Cramer E, Saladores P, Gorelick RJ, Guo J, Musier-Forsyth K, Levin JG (2009) Fidelity of plus-strand priming requires the nucleic acid chaperone activity of HIV-1 nucleocapsid protein. Nucleic Acids Res 37:1755–1766

    Article  PubMed  CAS  Google Scholar 

  143. Ramirez BC, Simon-Loriere E, Galetto R, Negroni M (2008) Implications of recombination for HIV diversity. Virus Res 134:64–73

    Article  PubMed  CAS  Google Scholar 

  144. Derebail SS, Heath MJ, DeStefano JJ (2003) Evidence for the differential effects of nucleocapsid protein on strand transfer in various regions of the HIV genome. J Biol Chem 278:15702–15712

    Article  PubMed  CAS  Google Scholar 

  145. Roda RH, Balakrishnan M, Kim JK, Roques BP, Fay PJ, Bambara RA (2002) Strand transfer occurs in retroviruses by a pause-initiated two-step mechanism. J Biol Chem 277:46900–46911

    Article  PubMed  CAS  Google Scholar 

  146. Fouchier RA, Malim MH (1999) Nuclear import of human immunodeficiency virus type-1 preintegration complexes. Adv Virus Res 52:275–299

    Article  PubMed  CAS  Google Scholar 

  147. Miller MD, Farnet CM, Bushman FD (1997) Human immunodeficiency virus type 1 preintegration complexes: studies of organization and composition. J Virol 71:5382–5390

    PubMed  CAS  Google Scholar 

  148. Bukrinsky M (2004) A hard way to the nucleus. Mol Med 10:1–5

    PubMed  CAS  Google Scholar 

  149. Oz I, Avidan O, Hizi A (2002) Inhibition of the integrases of human immunodeficiency viruses type 1 and type 2 by reverse transcriptases. Biochem J 361:557–566

    Article  PubMed  CAS  Google Scholar 

  150. Herschhorn A, Oz-Gleenberg I, Hizi A (2008) Quantitative analysis of the interactions between HIV-1 integrase and retroviral reverse transcriptases. Biochem J 412:163–170

    Article  PubMed  CAS  Google Scholar 

  151. Wilkinson TA, Januszyk K, Phillips ML, Tekeste SS, Zhang M, Miller JT, Le Grice SF, Clubb RT, Chow SA (2009) Identifying and characterizing a functional HIV-1 reverse transcriptase-binding site on integrase. J Biol Chem 284:7931–7939

    Article  PubMed  CAS  Google Scholar 

  152. Steele SJ, Levin HL (1998) A map of interactions between the proteins of a retrotransposon. J Virol 72:9318–9322

    PubMed  CAS  Google Scholar 

  153. Oz Gleenberg I, Avidan O, Goldgur Y, Herschhorn A, Hizi A (2005) Peptides derived from the reverse transcriptase of human immunodeficiency virus type 1 as novel inhibitors of the viral integrase. J Biol Chem 280:21987–21996

    Article  PubMed  CAS  Google Scholar 

  154. Oz Gleenberg I, Herschhorn A, Goldgur Y, Hizi A (2007) Inhibition of human immunodeficiency virus type-1 reverse transcriptase by a novel peptide derived from the viral integrase. Arch Biochem Biophys 458:202–212

    Article  PubMed  CAS  Google Scholar 

  155. Wu X, Liu H, Xiao H, Conway JA, Hehl E, Kalpana GV, Prasad V, Kappes JC (1999) Human immunodeficiency virus type 1 integrase protein promotes reverse transcription through specific interactions with the nucleoprotein reverse transcription complex. J Virol 73:2126–2135

    PubMed  CAS  Google Scholar 

  156. Gleenberg IO, Herschhorn A, Hizi A (2007) Inhibition of the activities of reverse transcriptase and integrase of human immunodeficiency virus type-1 by peptides derived from the homologous viral protein R (Vpr). J Mol Biol 369:1230–1243

    Article  PubMed  CAS  Google Scholar 

  157. Sire J, Querat G, Esnault C, Priet S (2008) Uracil within DNA: an actor of antiviral immunity. Retrovirology 5:45

    Article  PubMed  CAS  Google Scholar 

  158. Payne SL, Elder JH (2001) The role of retroviral dUTPases in replication and virulence. Curr Protein Pept Sci 2:381–388

    Article  PubMed  CAS  Google Scholar 

  159. Chen R, Wang H, Mansky LM (2002) Roles of uracil-DNA glycosylase and dUTPase in virus replication. J Gen Virol 83:2339–2345

    PubMed  CAS  Google Scholar 

  160. Willetts KE, Rey F, Agostini I, Navarro JM, Baudat Y, Vigne R, Sire J (1999) DNA repair enzyme uracil DNA glycosylase is specifically incorporated into human immunodeficiency virus type 1 viral particles through a Vpr-independent mechanism. J Virol 73:1682–1688

    PubMed  CAS  Google Scholar 

  161. Priet S, Navarro JM, Querat G, Sire J (2003) Reversion of the lethal phenotype of an HIV-1 integrase mutant virus by overexpression of the same integrase mutant protein. J Biol Chem 278:20724–20730

    Article  PubMed  CAS  Google Scholar 

  162. Priet S, Navarro JM, Gros N, Querat G, Sire J (2003) Functional role of HIV-1 virion-associated uracil DNA glycosylase 2 in the correction of G:U mispairs to G:C pairs. J Biol Chem 278:4566–4571

    Article  PubMed  CAS  Google Scholar 

  163. Priet S, Gros N, Navarro JM, Boretto J, Canard B, Querat G, Sire J (2005) HIV-1-associated uracil DNA glycosylase activity controls dUTP misincorporation in viral DNA and is essential to the HIV-1 life cycle. Mol Cell 17:479–490

    Article  PubMed  CAS  Google Scholar 

  164. Priet S, Navarro JM, Gros N, Querat G, Sire J (2003) Differential incorporation of uracil DNA glycosylase UNG2 into HIV-1, HIV-2, and SIV(MAC) viral particles. Virology 307:283–289

    Article  PubMed  CAS  Google Scholar 

  165. Malim MH (2009) APOBEC proteins and intrinsic resistance to HIV-1 infection. Philos Trans R Soc Lond B Biol Sci 364:675–687

    Article  PubMed  CAS  Google Scholar 

  166. Goila-Gaur R, Strebel K (2008) HIV-1 Vif, APOBEC, and intrinsic immunity. Retrovirology 5:51

    Article  PubMed  CAS  Google Scholar 

  167. Mangeat B, Turelli P, Caron G, Friedli M, Perrin L, Trono D (2003) Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts. Nature 424:99–103

    Article  PubMed  CAS  Google Scholar 

  168. Iwatani Y, Chan DS, Wang F, Maynard KS, Sugiura W, Gronenborn AM, Rouzina I, Williams MC, Musier-Forsyth K, Levin JG (2007) Deaminase-independent inhibition of HIV-1 reverse transcription by APOBEC3G. Nucleic Acids Res 35:7096–7108

    Article  PubMed  CAS  Google Scholar 

  169. Bishop KN, Holmes RK, Malim MH (2006) Antiviral potency of APOBEC proteins does not correlate with cytidine deamination. J Virol 80:8450–8458

    Article  PubMed  CAS  Google Scholar 

  170. Holmes RK, Koning FA, Bishop KN, Malim MH (2007) APOBEC3F can inhibit the accumulation of HIV-1 reverse transcription products in the absence of hypermutation. Comparisons with APOBEC3G. J Biol Chem 282:2587–2595

    Article  PubMed  CAS  Google Scholar 

  171. Mbisa JL, Barr R, Thomas JA, Vandegraaff N, Dorweiler IJ, Svarovskaia ES, Brown WL, Mansky LM, Gorelick RJ, Harris RS, Engelman A, Pathak VK (2007) Human immunodeficiency virus type 1 cDNAs produced in the presence of APOBEC3G exhibit defects in plus-strand DNA transfer and integration. J Virol 81:7099–7110

    Article  PubMed  CAS  Google Scholar 

  172. De Clercq E (2004) Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present, and future. Chem Biodivers 1:44–64

    Article  PubMed  Google Scholar 

  173. De Clercq E (2007) The design of drugs for HIV and HCV. Nat Rev Drug Discov 6:1001–1018

    Article  PubMed  CAS  Google Scholar 

  174. Ilina T, Parniak MA (2008) Inhibitors of HIV-1 reverse transcriptase. Adv Pharmacol 56:121–167

    Article  PubMed  CAS  Google Scholar 

  175. Gao HQ, Boyer PL, Sarafianos SG, Arnold E, Hughes SH (2000) The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase. J Mol Biol 300:403–418

    Article  PubMed  CAS  Google Scholar 

  176. Sarafianos SG, Das K, Clark AD Jr, Ding J, Boyer PL, Hughes SH, Arnold E (1999) Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci USA 96:10027–10032

    Article  PubMed  CAS  Google Scholar 

  177. Halvas EK, Svarovskaia ES, Freed EO, Pathak VK (2000) Wild-type and YMDD mutant murine leukemia virus reverse transcriptases are resistant to 2′,3′-dideoxy-3′-thiacytidine. J Virol 74:6669–6674

    Article  PubMed  CAS  Google Scholar 

  178. Boyer PL, Sarafianos SG, Arnold E, Hughes SH (2001) Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J Virol 75:4832–4842

    Article  PubMed  CAS  Google Scholar 

  179. Sluis-Cremer N, Arion D, Parikh U, Koontz D, Schinazi RF, Mellors JW, Parniak MA (2005) The 3′-azido group is not the primary determinant of 3′-azido-3′-deoxythymidine (AZT) responsible for the excision phenotype of AZT-resistant HIV-1. J Biol Chem 280:29047–29052

    Article  PubMed  CAS  Google Scholar 

  180. Boyer PL, Sarafianos SG, Clark PK, Arnold E, Hughes SH (2006) Why do HIV-1 and HIV-2 use different pathways to develop AZT resistance? PLoS Pathog 2:e10

    Article  PubMed  CAS  Google Scholar 

  181. Deval J, Alvarez K, Selmi B, Bermond M, Boretto J, Guerreiro C, Mulard L, Canard B (2005) Mechanistic insights into the suppression of drug resistance by human immunodeficiency virus type 1 reverse transcriptase using alpha-boranophosphate nucleoside analogs. J Biol Chem 280:3838–3846

    Article  PubMed  CAS  Google Scholar 

  182. Deval J, Selmi B, Boretto J, Egloff MP, Guerreiro C, Sarfati S, Canard B (2002) The molecular mechanism of multidrug resistance by the Q151M human immunodeficiency virus type 1 reverse transcriptase and its suppression using alpha-boranophosphate nucleotide analogues. J Biol Chem 277:42097–42104

    Article  PubMed  CAS  Google Scholar 

  183. Selmi B, Boretto J, Sarfati SR, Guerreiro C, Canard B (2001) Mechanism-based suppression of dideoxynucleotide resistance by K65R human immunodeficiency virus reverse transcriptase using an alpha-boranophosphate nucleoside analogue. J Biol Chem 276:48466–48472

    PubMed  CAS  Google Scholar 

  184. Meyer P, Schneider B, Sarfati S, Deville-Bonne D, Guerreiro C, Boretto J, Janin J, Veron M, Canard B (2000) Structural basis for activation of alpha-boranophosphate nucleotide analogues targeting drug-resistant reverse transcriptase. EMBO J 19:3520–3529

    Article  PubMed  CAS  Google Scholar 

  185. Schneider B, Meyer P, Sarfati S, Mulard L, Guerreiro C, Boretto J, Janin J, Veron M, Deville-Bonne D, Canard B (2001) Activation of anti-reverse transcriptase nucleotide analogs by nucleoside diphosphate kinase: improvement by alpha-boranophosphate substitution. Nucleosides Nucleotides Nucleic Acids 20:297–306

    Article  PubMed  CAS  Google Scholar 

  186. Boyer PL, Julias JG, Marquez VE, Hughes SH (2005) Fixed conformation nucleoside analogs effectively inhibit excision-proficient HIV-1 reverse transcriptases. J Mol Biol 345:441–450

    Article  PubMed  CAS  Google Scholar 

  187. Murakami E, Basavapathruni A, Bradley WD, Anderson KS (2005) Mechanism of action of a novel viral mutagenic covert nucleotide: molecular interactions with HIV-1 reverse transcriptase and host cell DNA polymerases. Antiviral Res 67:10–17

    Article  PubMed  CAS  Google Scholar 

  188. Harris KS, Brabant W, Styrchak S, Gall A, Daifuku R (2005) KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res 67:1–9

    Article  PubMed  CAS  Google Scholar 

  189. Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI, Stammers DK (2001) Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors. J Mol Biol 312:795–805

    Article  PubMed  CAS  Google Scholar 

  190. Das K, Lewi PJ, Hughes SH, Arnold E (2005) Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors. Prog Biophys Mol Biol 88:209–231

    Article  PubMed  CAS  Google Scholar 

  191. Sarafianos SG, Das K, Hughes SH, Arnold E (2004) Taking aim at a moving target: designing drugs to inhibit drug-resistant HIV-1 reverse transcriptases. Curr Opin Struct Biol 14:716–730

    Article  PubMed  CAS  Google Scholar 

  192. Das K, Clark AD Jr, Lewi PJ, Heeres J, De Jonge MR, Koymans LM, Vinkers HM, Daeyaert F, Ludovici DW, Kukla MJ, De Corte B, Kavash RW, Ho CY, Ye H, Lichtenstein MA, Andries K, Pauwels R, De Bethune MP, Boyer PL, Clark P, Hughes SH, Janssen PA, Arnold E (2004) Roles of conformational and positional adaptability in structure-based design of TMC125–R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J Med Chem 47:2550–2560

    Article  PubMed  CAS  Google Scholar 

  193. Vingerhoets J, Azijn H, Fransen E, De Baere I, Smeulders L, Jochmans D, Andries K, Pauwels R, de Bethune MP (2005) TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J Virol 79:12773–12782

    Article  PubMed  CAS  Google Scholar 

  194. Das K, Bauman JD, Clark AD Jr, Frenkel YV, Lewi PJ, Shatkin AJ, Hughes SH, Arnold E (2008) High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci USA 105:1466–1471

    Article  PubMed  Google Scholar 

  195. Ren J, Stammers DK (2008) Structural basis for drug resistance mechanisms for non-nucleoside inhibitors of HIV reverse transcriptase. Virus Res 134:157–170

    Article  PubMed  CAS  Google Scholar 

  196. Hsiou Y, Ding J, Das K, Clark AD Jr, Boyer PL, Lewi P, Janssen PA, Kleim JP, Rosner M, Hughes SH, Arnold E (2001) The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J Mol Biol 309:437–445

    Article  PubMed  CAS  Google Scholar 

  197. Sluis-Cremer N, Tachedjian G (2008) Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res 134:147–156

    Article  PubMed  CAS  Google Scholar 

  198. Ren J, Diprose J, Warren J, Esnouf RM, Bird LE, Ikemizu S, Slater M, Milton J, Balzarini J, Stuart DI, Stammers DK (2000) Phenylethylthiazolylthiourea (PETT) non-nucleoside inhibitors of HIV-1 and HIV-2 reverse transcriptases. Structural and biochemical analyses. J Biol Chem 275:5633–5639

    Article  PubMed  CAS  Google Scholar 

  199. Himmel DM, Sarafianos SG, Dharmasena S, Hossain MM, McCoy-Simandle K, Ilina T, Clark AD Jr, Knight JL, Julias JG, Clark PK, Krogh-Jespersen K, Levy RM, Hughes SH, Parniak MA, Arnold E (2006) HIV-1 reverse transcriptase structure with RNase H inhibitor dihydroxy benzoyl naphthyl hydrazone bound at a novel site. ACS Chem Biol 1:702–712

    Article  PubMed  CAS  Google Scholar 

  200. Hachiya A, Kodama EN, Sarafianos SG, Schuckmann MM, Sakagami Y, Matsuoka M, Takiguchi M, Gatanaga H, Oka S (2008) Amino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J Virol 82:3261–3270

    Article  PubMed  CAS  Google Scholar 

  201. Herschhorn A, Hizi A (2008) Virtual screening, identification, and biochemical characterization of novel inhibitors of the reverse transcriptase of human immunodeficiency virus type-1. J Med Chem 51:5702–5713

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to Drs. Iris Oz-Gleenberg and Shoshana Loya for critically reading the manuscript and for helpful suggestions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amnon Hizi.

Additional information

A. Hizi: Incumbent of the Gregorio and Dora Shapira Chair for the Research of Malignancies.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Herschhorn, A., Hizi, A. Retroviral reverse transcriptases. Cell. Mol. Life Sci. 67, 2717–2747 (2010). https://doi.org/10.1007/s00018-010-0346-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-010-0346-2

Keywords

Navigation