HIV Reverse Transcriptase Fidelity, Clade Diversity, and Acquisition of Drug Resistance



The human immunodeficiency virus (HIV) is a lentivirus (a member of the family Retroviridae) that causes acquired immunodeficiency syndrome (AIDS) in humans. Two types of HIV have been identified, HIV-1 and HIV-2. Genetic variability is one of the hallmarks of HIV. Its genetic diversity is manifested worldwide through the identification of numerous clades as well as within individuals, where pairwise comparisons of viral sequences revealed differences of up to 2.5 %. HIV-1 variants have been classified into four major phylogenetic groups: M (main), O (outlier), N (non-M/non-O), and P. The M group includes at least nine genetically distinct clades, designated as subtypes A, B, C, D, F, G, H, J, and K (Buonaguro et al. 2007; Ramirez et al. 2008; Plantier et al. 2009) (Fig. 11.1). Subtype B (group M) includes the first HIV isolates identified in the early 80s and is the most prevalent clade in Western Europe and the Americas (Hemelaar et al. 2011). Therefore, most virological studies and characterizations of HIV-1 proteins have been carried out with reference laboratory strains belonging to group M subtype B.


Human Immunodeficiency Virus Murine Leukemia Virus Equine Infectious Anemia Virus Rous Sarcoma Virus Murine Leukemia Virus Reverse Transcriptase 
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.



I thank past and present members of our group and collaborators elsewhere for their contribution to RT fidelity studies over the years. I also thank Verónica Barrioluengo for her assistance in the preparation of Fig. 11.2. This work was supported in part by the Ministry of Science and Innovation of Spain (grant BIO2010/15542) and an institutional grant from the Fundación Ramón Areces.


  1. Abram ME, Ferris AL, Shao W, Alvord WG, Hughes SH (2010) Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J Virol 84:9864–9878PubMedCrossRefGoogle Scholar
  2. Aguiar RS, Peterlin BM (2008) APOBEC3 proteins and reverse transcription. Virus Res 134:74–85PubMedCrossRefGoogle Scholar
  3. Álvarez M, Matamoros T, Menéndez-Arias L (2009) Increased thermostability and fidelity of DNA synthesis of wild-type and mutant HIV-1 group O reverse transcriptases. J Mol Biol 392:872–884PubMedCrossRefGoogle Scholar
  4. Anderson JP, Daifuku R, Loeb LA (2004) Viral error catastrophe by mutagenic nucleosides. Annu Rev Microbiol 58:183–205PubMedCrossRefGoogle Scholar
  5. Arezi B, Hogrefe H (2009) Novel mutations in Moloney murine leukemia virus reverse transcriptase increase thermostability through tighter binding to template-primer. Nucleic Acids Res 37:473–481PubMedCrossRefGoogle Scholar
  6. Back NKT, Nijhuis M, Keulen W, Boucher CAB, Oude Essink BB, van Kuilenburg ABP, van Gennip AH, Berkhout B (1996) Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J 15:4040–4049PubMedGoogle Scholar
  7. 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 31:9393–9398PubMedCrossRefGoogle Scholar
  8. 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 319:201–205PubMedCrossRefGoogle Scholar
  9. Baltimore D (1970) RNA-dependent DNA polymerase in virions of RNA tumour viruses. Nature 226:1209–1211PubMedCrossRefGoogle Scholar
  10. Balzarini J, Camarasa M-J, Pérez-Pérez M-J, San-Félix A, Velázquez S, Perno C-F, De Clercq E, Anderson JN, Karlsson A (2001) 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 75:5772–5777PubMedCrossRefGoogle Scholar
  11. Bampi C, Bibillo A, Wendeler M, Divita G, Gorelick RJ, Le Grice SFJ, Darlix J-L (2006) Nucleotide excision repair and template-independent addition by HIV-1 reverse transcriptase in the presence of nucleocapsid protein. J Biol Chem 281:11736–11743PubMedCrossRefGoogle Scholar
  12. Barrioluengo V, Álvarez M, Barbieri D, Menéndez-Arias L (2011) Thermostable HIV-1 group O reverse transcriptase variants with the same fidelity as murine leukaemia virus reverse transcriptase. Biochem J 436:599–607PubMedCrossRefGoogle Scholar
  13. Barrioluengo V, Wang Y, Le Grice SFJ, Menéndez-Arias L (2012) Intrinsic DNA synthesis fidelity of xenotropic murine leukemia virus-related virus reverse transcriptase. FEBS J 279:1433–1444PubMedCrossRefGoogle Scholar
  14. Beard WA, Stahl SJ, Kim H-R, Bebenek K, Kumar A, Strub M-P, Becerra SP, Kunkel TA, Wilson SH (1994) Structure/function studies of human immunodeficiency virus type 1 reverse transcriptase – alanine scanning mutagenesis of an α-helix in the thumb subdomain. J Biol Chem 269:28091–28097PubMedGoogle Scholar
  15. Bebenek K, Kunkel TA (1995) Analyzing fidelity of DNA polymerases. Methods Enzymol 262:217–232PubMedCrossRefGoogle Scholar
  16. Bebenek K, Abbotts J, Roberts JD, Wilson SH, Kunkel TA (1989) Specificity and mechanism of error-prone replication by human immunodeficiency virus-1 reverse transcriptase. J Biol Chem 264:16948–16956PubMedGoogle Scholar
  17. Bebenek K, Abbotts J, Wilson SH, Kunkel TA (1993) Error-prone polymerization by HIV-1 reverse transcriptase – contribution of template-primer misalignment, miscoding, and termination probability to mutational hot spots. J Biol Chem 268:10324–10334PubMedGoogle Scholar
  18. Bebenek K, Beard WA, Casas-Finet JR, Kim H-R, Darden TA, Wilson SH, Kunkel TA (1995) Reduced frameshift fidelity and processivity of HIV-1 reverse transcriptase mutants containing alanine substitutions in helix H of the thumb subdomain. J Biol Chem 270:19516–19523PubMedCrossRefGoogle Scholar
  19. Boyer PL, Hughes SH (2000) Effects of amino acid substitutions at position 115 on the fidelity of human immunodeficiency virus type 1 reverse transcriptase. J Virol 74:6494–6500PubMedCrossRefGoogle Scholar
  20. Boyer JC, Bebenek K, Kunkel TA (1992) Unequal human immunodeficiency virus type 1 reverse transcriptase error rates with RNA and DNA templates. Proc Natl Acad Sci USA 89:6919–6923PubMedCrossRefGoogle Scholar
  21. Boyer PL, Stenbak CR, Hoberman D, Linial ML, Hughes SH (2007) In vitro fidelity of the prototype primate foamy virus (PFV) RT compared to HIV-1 RT. Virology 367:253–264PubMedCrossRefGoogle Scholar
  22. Buonaguro L, Tornesello ML, Buonaguro FM (2007) Human immunodeficiency virus type 1 subtype distribution in the worldwide epidemic: pathogenetic and therapeutic implications. J Virol 81:10209–10219PubMedCrossRefGoogle Scholar
  23. Cases-González CE, Menéndez-Arias L (2004) Increased G → A transition frequencies displayed by primer grip mutants of human immunodeficiency virus type 1 reverse transcriptase. J Virol 78:1012–1019PubMedCrossRefGoogle Scholar
  24. Cases-González CE, Gutiérrez-Rivas M, Menéndez-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 275:19759–19767PubMedCrossRefGoogle Scholar
  25. Coffey LL, Beeharry Y, Bordería AV, Blanc H, Vignuzzi M (2011) Arbovirus high fidelity variant loses fitness in mosquitoes and mice. Proc Natl Acad Sci USA 108:16038–16043PubMedCrossRefGoogle Scholar
  26. Curr K, Tripathi S, Lennerstrand J, Larder BA, Prasad VR (2006) Influence of naturally occurring insertions in the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and mutation frequencies in vitro. J Gen Virol 87:419–428PubMedCrossRefGoogle Scholar
  27. Dapp MJ, Clouser CL, Patterson S, Mansky LM (2009) 5-Azacytidine can induce lethal mutagenesis in human immunodeficiency virus type 1. J Virol 83:11950–11958PubMedCrossRefGoogle Scholar
  28. Diamond TL, Kimata J, Kim B (2001) Identification of a simian immunodeficiency virus reverse transcriptase variant with enhanced replicational fidelity in the late stage of viral infection. J Biol Chem 276:23624–23631PubMedCrossRefGoogle Scholar
  29. Diamond TL, Souroullas G, Weiss KK, Lee KY, Bambara RA, Dewhurst S, Kim B (2003) Mechanistic understanding of an altered fidelity simian immunodeficiency virus reverse transcriptase mutation, V148I, identified in a pig-tailed macaque. J Biol Chem 278:29913–29924PubMedCrossRefGoogle Scholar
  30. Domingo E, Escarmís C, Lázaro E, Manrubia SC (2005) Quasispecies dynamics and RNA virus extinction. Virus Res 107:129–139PubMedCrossRefGoogle Scholar
  31. Drosopoulos WC, Prasad VR (1998) Increased misincorporation fidelity observed for nucleoside analog resistance mutations M184V and E89G in human immunodeficiency virus type 1 reverse transcriptase does not correlate with the overall error rate measured in vitro. J Virol 72:4224–4230PubMedGoogle Scholar
  32. Duran-Reynals F (1942) The reciprocal infection of ducks and chickens with tumor-inducing viruses. Cancer Res 2:343–369Google Scholar
  33. Echols H, Goodman MF (1991) Fidelity mechanisms in DNA replication. Annu Rev Biochem 60:477–511PubMedCrossRefGoogle Scholar
  34. Eckert KA, Kunkel TA (1993) Fidelity of DNA synthesis catalyzed by human DNA polymerase α and HIV-1 reverse transcriptase: effect of reaction pH. Nucleic Acids Res 21:5212–5220PubMedCrossRefGoogle Scholar
  35. Elder JH, Lerner DL, Hasselkus-Light CS, Fontenot DJ, Hunter E, Luciw PA, Montelaro RC, Phillips TR (1992) Distinct subsets of retroviruses encode dUTPase. J Virol 66:1791–1794PubMedGoogle Scholar
  36. Gago S, Elena SF, Flores R, Sanjuán R (2009) Extremely high mutation rate of a hammerhead viroid. Science 323:1308PubMedCrossRefGoogle Scholar
  37. 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 94:407–411PubMedCrossRefGoogle Scholar
  38. Gao F, Chen Y, Levy DN, Conway JA, Kepler TB, Hui H (2004) Unselected mutations in the human immunodeficiency virus type 1 genome are mostly nonsynonymous and often deleterious. J Virol 78:2426–2433PubMedCrossRefGoogle Scholar
  39. Garforth SJ, Domaoal RA, Lwatula C, Landau MJ, Meyer AJ, Anderson KS, Prasad VR (2010) K65R and K65A substitutions in HIV-1 reverse transcriptase enhance polymerase fidelity by decreasing both dNTP misinsertion and mispaired primer extension efficiencies. J Mol Biol 401:33–44PubMedCrossRefGoogle Scholar
  40. Gärtner K, Wiktorowicz T, Park J, Mergia A, Rethwilm A, Scheller C (2009) Accuracy estimation of foamy virus genome copying. Retrovirology 6:32PubMedCrossRefGoogle Scholar
  41. Gerard GF, Potter RJ, Smith MD, Rosenthal K, Dhariwal G, Lee J, Chatterjee DK (2002) The role of template-primer in protection of reverse transcriptase from thermal inactivation. Nucleic Acids Res 30:3118–3129PubMedCrossRefGoogle Scholar
  42. Godet J, Ramalanjaona N, Sharma KK, Richert L, de Rocquigny H, Darlix J-L, Duportail G, Mély Y (2011) Specific implications of the HIV-1 nucleocapsid zinc fingers in the annealing of the primer binding site complementary sequences during the obligatory plus strand transfer. Nucleic Acids Res 39:6633–6645PubMedCrossRefGoogle Scholar
  43. Grohmann D, Godet J, Mély Y, Darlix J-L, Restle T (2008) HIV-1 nucleocapsid traps reverse transcriptase on nucleic acid substrates. Biochemistry 47:12230–12240PubMedCrossRefGoogle Scholar
  44. Hamburgh ME, Curr KA, Monaghan M, Rao VR, Tripathi S, Preston BD, Sarafianos S, Arnold E, Darden T, Prasad VR (2006) Structural determinants of slippage-mediated mutations by human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem 281:7421–7428PubMedCrossRefGoogle Scholar
  45. Harris D, Kaushik N, Pandey PK, Yadav PN, Pandey VN (1998) Functional analysis of amino acid residues constituting the dNTP binding pocket of HIV-1 reverse transcriptase. J Biol Chem 273:33624–33634PubMedCrossRefGoogle Scholar
  46. Hemelaar J, Gouws E, Ghys PD, Osmanov S, WHO-UNAIDS network for HIV Isolation and Characterisation (2011) Global trends in molecular epidemiology of HIV-1 during 2000–2007. AIDS 25:679–689PubMedCrossRefGoogle Scholar
  47. Herschhorn A, Hizi A (2010) Retroviral reverse transcriptases. Cell Mol Life Sci 67:2717–2747PubMedCrossRefGoogle Scholar
  48. Huang KJ, Wooley DP (2005) A new cell-based assay for measuring the forward mutation rate of HIV-1. J Virol Methods 124:95–104PubMedCrossRefGoogle Scholar
  49. 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 282:1669–1675PubMedCrossRefGoogle Scholar
  50. 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 Å resolution shows bent DNA. Proc Natl Acad Sci USA 90:6320–6324PubMedCrossRefGoogle Scholar
  51. Jamburuthugoda VK, Eickbush TH (2011) The reverse transcriptase encoded by the non-LTR retrotransposon R2 is as error-prone as that encoded by HIV-1. J Mol Biol 407:661–672PubMedCrossRefGoogle Scholar
  52. Jamburuthugoda VK, Guo D, Wedekind JE, Kim B (2005) Kinetic evidence for interaction of human immunodeficiency virus type 1 reverse transcriptase with the 3′-OH of the incoming dTTP substrate. Biochemistry 44:10635–10643PubMedCrossRefGoogle Scholar
  53. Jern P, Russell RA, Pathak VK, Coffin JM (2009) Likely role of APOBEC3G-mediated G-to-A mutations in HIV-1 evolution and drug resistance. PLoS Pathog 5:e1000367PubMedCrossRefGoogle Scholar
  54. Ji J, Loeb LA (1992) Fidelity of HIV-1 reverse transcriptase copying RNA in vitro. Biochemistry 31:954–958PubMedCrossRefGoogle Scholar
  55. Ji J, Loeb LA (1994) Fidelity of HIV-1 reverse transcriptase copying a hypervariable region of the HIV-1 env gene. Virology 199:323–330PubMedCrossRefGoogle Scholar
  56. Johnson KA (1993) Conformational coupling in DNA polymerase fidelity. Annu Rev Biochem 62:685–713PubMedCrossRefGoogle Scholar
  57. Jonckheere H, Witvrouw M, De Clercq E, Anné J (1998) Lamivudine resistance of HIV type 1 does not delay development of resistance to nonnucleoside HIV type 1-specific reverse transcriptase inhibitors as compared with wild-type HIV type 1. AIDS Res Hum Retroviruses 14:249–253PubMedCrossRefGoogle Scholar
  58. Jonckheere H, De Clercq E, Anné J (2000) Fidelity analysis of HIV-1 reverse transcriptase mutants with an altered amino-acid sequence at residues Leu74, Glu89, Tyr115, Tyr183 and Met184. Eur J Biochem 267:2658–2665PubMedCrossRefGoogle Scholar
  59. Julias JG, Pathak VK (1998) Deoxyribonucleoside triphosphate pool imbalances in vivo are associated with an increased retroviral mutation rate. J Virol 72:7941–7949PubMedGoogle Scholar
  60. Julias JG, Kim T, Arnold G, Pathak VK (1997) The antiretrovirus drug 3′-azido-3′-deoxythymidine increases the retrovirus mutation rate. J Virol 71:4254–4263PubMedGoogle Scholar
  61. Kati WM, Johnson KA, Jerva LF, Anderson KS (1992) Mechanism and fidelity of HIV reverse transcriptase. J Biol Chem 267:25988–25997PubMedGoogle Scholar
  62. Kellinger MW, Johnson KA (2010) Nucleotide-dependent conformational change governs specificity and analog discrimination by HIV reverse transcriptase. Proc Natl Acad Sci USA 107:7734–7739PubMedCrossRefGoogle Scholar
  63. Kerr SG, Anderson KS (1997) RNA dependent DNA replication fidelity of HIV-1 reverse transcriptase: evidence of discrimination between DNA and RNA substrates. Biochemistry 36:14056–14063PubMedCrossRefGoogle Scholar
  64. Keulen W, van Wijk A, Schuurman R, Berkhout B, Boucher CAB (1999) Increased polymerase fidelity of lamivudine-resistant HIV-1 variants does not limit their evolutionary potential. AIDS 13:1343–1349PubMedCrossRefGoogle Scholar
  65. Kim T, Mudry RA Jr, Rexrode CA 2nd, Pathak VK (1996) Retroviral mutation rates and A-to-G hypermutations during different stages of retroviral replication. J Virol 70:7594–7602PubMedGoogle Scholar
  66. Kim J, Roberts A, Yuan H, Xiong Y, Anderson KS (2012) Nucleocapsid protein annealing of a primer-template enhances (+)-strand DNA synthesis and fidelity by HIV-1 reverse transcriptase. J Mol Biol 415:866–880PubMedCrossRefGoogle Scholar
  67. Kisic M, Matamoros T, Nevot M, Mendieta J, Martinez-Picado J, Martínez MA, Menéndez-Arias L (2011) Thymidine analogue excision and discrimination modulated by mutational complexes including single amino acid deletions of Asp-67 or Thr-69 in HIV-1 reverse transcriptase. J Biol Chem 286:20615–20624PubMedCrossRefGoogle Scholar
  68. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA (1992) Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256:1783–1790PubMedCrossRefGoogle Scholar
  69. Köppe B, Menéndez-Arias L, Oroszlan S (1994) Expression and purification of the mouse mammary tumor virus gag-pro transframe protein p30 and characterization of its dUTPase activity. J Virol 68:2313–2319PubMedGoogle Scholar
  70. Kumar D, Abdulovic AL, Viberg J, Nilsson AK, Kunkel TA, Chabes A (2011) Mechanisms of mutagenesis in vivo due to imbalanced dNTP pools. Nucleic Acids Res 39:1360–1371PubMedCrossRefGoogle Scholar
  71. Kunkel TA (2004) DNA replication fidelity. J Biol Chem 279:16895–16898PubMedCrossRefGoogle Scholar
  72. Kunkel TA, Bebenek K (2000) DNA replication fidelity. Annu Rev Biochem 69:497–529PubMedCrossRefGoogle Scholar
  73. Laakso MM, Sutton RE (2006) Replicative fidelity of lentiviral vectors produced by transient infection. Virology 348:406–417PubMedCrossRefGoogle Scholar
  74. LaCasse RA, Remington KM, North TW (1996) The mutation frequency of feline immunodeficiency virus enhanced by 3′-azido-3′-deoxythymidine. J Acquir Immune Defic Syndr Hum Retrovirol 12:26–32PubMedCrossRefGoogle Scholar
  75. Lee HY, Perelson AS, Park S-C, Leitner T (2008) Dynamic correlation between intrahost HIV-1 quasispecies evolution and disease progression. PLoS Comput Biol 4:e1000240PubMedCrossRefGoogle Scholar
  76. Leider JM, Palese P, Smith FI (1988) Determination of the mutation rate of a retrovirus. J Virol 62:3084–3091PubMedGoogle Scholar
  77. Levin JG, Mitra M, Mascarenhas A, Musier-Forsyth K (2010) Role of HIV-1 nucleocapsid protein in HIV-1 reverse transcription. RNA Biol 7:754–774PubMedCrossRefGoogle Scholar
  78. Lewis DA, Bebenek K, Beard WA, Wilson SH, Kunkel TA (1999) Uniquely altered DNA replication fidelity conferred by an amino acid change in the nucleotide binding pocket of human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem 274:32924–32930PubMedCrossRefGoogle Scholar
  79. Loeb LA, Essigmann JM, Kazazi F, Zhang J, Rose KD, Mullins JI (1999) Lethal mutagenesis of HIV with mutagenic nucleoside analogs. Proc Natl Acad Sci USA 96:1492–1497PubMedCrossRefGoogle Scholar
  80. Lwatula C, Garforth SJ, Prasad VR (2012) Lys66 residue as a determinant of high mismatch extension and misinsertion rates of HIV-1 reverse transcriptase. FEBS J 279:4010–4024 Lynch M (2006) The origins of eukaryotic gene structure. Mol Biol Evol 23:450–468PubMedCrossRefGoogle Scholar
  81. Malboeuf CM, Isaacs SJ, Tran NH, Kim B (2001) Thermal effects on reverse transcription: improvement of accuracy and processivity in cDNA synthesis. Biotechniques 30:1074–1084PubMedGoogle Scholar
  82. Mansky LM (1996) Forward mutation rate of human immunodeficiency virus type 1 in a T lymphoid cell line. AIDS Res Hum Retroviruses 12:307–314PubMedCrossRefGoogle Scholar
  83. Mansky LM, Bernard LC (2000) 3′-azido-3′-deoxythymidine (AZT) and AZT-resistant reverse transcriptase can increase the in vivo mutation rate of human immunodeficiency virus type 1. J Virol 74:9532–9539PubMedCrossRefGoogle Scholar
  84. Mansky LM, Temin HM (1995) Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 69:5087–5094PubMedGoogle Scholar
  85. 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 74:7039–7047PubMedCrossRefGoogle Scholar
  86. Mansky LM, Le Rouzic E, Benichou S, Gajary LC (2003) Influence of reverse transcriptase variants, drugs, and Vpr on human immunodeficiency virus type 1 mutant frequencies. J Virol 77:2071–2080PubMedCrossRefGoogle Scholar
  87. Martinez MA, Vartanian JP, Wain-Hobson S (1994) Hypermutagenesis of RNA using human immunodeficiency virus type 1 reverse transcriptase and biased dNTP concentrations. Proc Natl Acad Sci USA 91:11787–11791PubMedCrossRefGoogle Scholar
  88. Martín-Hernández AM, Domingo E, Menéndez-Arias L (1996) Human immunodeficiency virus type 1 reverse transcriptase: role of Tyr115 in deoxynucleotide binding and misinsertion fidelity of DNA synthesis. EMBO J 15:4434–4442PubMedGoogle Scholar
  89. Martín-Hernández AM, Gutiérrez-Rivas M, Domingo E, Menéndez-Arias L (1997) Mispair extension fidelity of human immunodeficiency virus type 1 reverse transcriptases with amino acid substitutions affecting Tyr115. Nucleic Acids Res 25:1383–1389PubMedCrossRefGoogle Scholar
  90. Matamoros T, Kim B, Menéndez-Arias L (2008) Mechanistic insights into the role of Val75 of HIV-1 reverse transcriptase in misinsertion and mispair extension fidelity of DNA synthesis. J Mol Biol 375:1234–1248PubMedCrossRefGoogle Scholar
  91. Matamoros T, Álvarez M, Barrioluengo V, Betancor G, Menéndez-Arias L (2011) Reverse transcriptase and retroviral replication. In: Kušić-Tišma J (ed) DNA replication and related cellular process. InTech, Rijeka, p. 111–142. Available from
  92. Matsuda T, Bebenek K, Masutani C, Hanaoka F, Kunkel TA (2000) Low fidelity DNA synthesis by human DNA polymerase-η. Nature 404:1011–1013PubMedCrossRefGoogle Scholar
  93. Mbisa JL, Nikolenko GN, Pathak VK (2005) Mutations in the RNase H primer grip domain of murine leukemia virus reverse transcriptase decrease efficiency and accuracy of plus-strand DNA transfer. J Virol 79:419–427PubMedCrossRefGoogle Scholar
  94. McCulloch SD, Kunkel TA (2008) The fidelity of DNA synthesis by eukaryotic replicative and translation synthesis polymerases. Cell Res 18:148–161PubMedCrossRefGoogle Scholar
  95. Mendelman LV, Boosalis MS, Petruska J, Goodman MF (1989) Nearest neighbor influences on DNA polymerase insertion fidelity. J Biol Chem 264:14415–14423PubMedGoogle Scholar
  96. Mendieta J, Cases-González CE, Matamoros T, Ramírez G, Menéndez-Arias L (2008) A Mg2+-induced conformational switch rendering a competent DNA polymerase catalytic complex. Proteins 71:565–574PubMedCrossRefGoogle Scholar
  97. Menéndez-Arias L (2002) Molecular basis of fidelity of DNA synthesis and nucleotide specificity of retroviral reverse transcriptases. Prog Nucleic Acid Res Mol Biol 71:91–147PubMedCrossRefGoogle Scholar
  98. Menéndez-Arias L (2008) Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res 134:124–146PubMedCrossRefGoogle Scholar
  99. Menéndez-Arias L (2009) Mutation rates and intrinsic fidelity of retroviral reverse transcriptases. Viruses 1:1137–1165PubMedCrossRefGoogle Scholar
  100. Menéndez-Arias L (2010) Molecular basis of human immunodeficiency virus drug resistance: an update. Antiviral Res 85:210–231PubMedCrossRefGoogle Scholar
  101. Menéndez-Arias L (2013) Molecular basis of human immunodeficiency virus type 1 drug resistance: overview and recent developments. Antiviral Res 98:93–120 Menéndez-Arias L, Abraha A, Quiñones-Mateu ME, Mas A, Camarasa M-J, Arts EJ (2001) Functional characterization of chimeric reverse transcriptases with polypeptide subunits of highly divergent HIV-1 group M and O strains. J Biol Chem 276:27470–27479PubMedCrossRefGoogle Scholar
  102. Menéndez-Arias L, Martínez MA, Quiñones-Mateu ME, Martinez-Picado J (2003) Fitness variations and their impact on the evolution of antiretroviral drug resistance. Curr Drug Targets Infect Disord 3:355–371PubMedCrossRefGoogle Scholar
  103. Monk RJ, Malik FG, Stokesberry D, Evans LH (1992) Direct determination of the point mutation rate of a murine retrovirus. J Virol 66:3683–3689PubMedGoogle Scholar
  104. Mulder LCF, Harari A, Simon V (2008) Cytidine deamination induced HIV-1 drug resistance. Proc Natl Acad Sci USA 105:5501–5506PubMedCrossRefGoogle Scholar
  105. Mullins JI, Heath L, Hughes JP, Kicha J, Styrchak S, Wong KG, Rao U, Hansen A, Harris KS, Laurent JP, Li D, Simpson JH, Essigmann JM, Loeb LA, Parkins J (2011) Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461. PLoS One 6:e15135PubMedCrossRefGoogle Scholar
  106. Ndongwe TP, Adedeji AO, Michailidis E, Ong YT, Hachiya A, Marchand B, Ryan EM, Rai DK, Kirby KA, Whatley AS, Burke DH, Johnson M, Ding S, Zheng Y-M, Liu S-L, Kodama E-I, Delviks-Frankenberry KA, Pathak VK, Mitsuya H, Parniak MA, Singh K, Sarafianos SG (2012) Biochemical, inhibition and inhibitor resistance studies of xenotropic murine leukemia virus-related virus reverse transcriptase. Nucleic Acids Res 40:345–359PubMedCrossRefGoogle Scholar
  107. O’Neil PK, Sun G, Yu H, Ron Y, Dougherty JP, Preston BD (2002) Mutational analysis of HIV-1 long terminal repeats to explore the relative contribution of reverse transcriptase and RNA polymerase II to viral mutagenesis. J Biol Chem 277:38053–38061PubMedCrossRefGoogle Scholar
  108. Operario DJ, Reynolds HM, Kim B (2005) Comparison of DNA polymerase activities between recombinant feline immunodeficiency and leukemia virus reverse transcriptases. Virology 335:106–121PubMedCrossRefGoogle Scholar
  109. Pathak VK, Temin HM (1992) 5-Azacytidine and RNA secondary structure increase the retrovirus mutation rate. J Virol 66:3093–3100PubMedGoogle Scholar
  110. Perrino FW, Preston BD, Sandell LL, Loeb LA (1989) Extension of mismatched 3′ termini of DNA is a major determinant of the infidelity of human immunodeficiency virus type 1 reverse transcriptase. Proc Natl Acad Sci USA 86:8343–8347PubMedCrossRefGoogle Scholar
  111. Plantier JC, Leoz M, Dickerson JE, De Oliveira F, Cordonnier F, Lemée V, Damond F, Robertson DL, Simon F (2009) A new human immunodeficiency virus derived from gorillas. Nat Med 15:871–872PubMedCrossRefGoogle Scholar
  112. 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 37:1755–1766PubMedCrossRefGoogle Scholar
  113. Preston BD, Poiesz BJ, Loeb LA (1988) Fidelity of HIV-1 reverse transcriptase. Science 242:1168–1171PubMedCrossRefGoogle Scholar
  114. Quiñones-Mateu ME, Soriano V, Domingo E, Menéndez-Arias L (1997) Characterization of the reverse transcriptase of a human immunodeficiency virus type 1 group O isolate. Virology 236:364–373PubMedCrossRefGoogle Scholar
  115. Ramirez BC, Simon-Loriere E, Galetto R, Negroni M (2008) Implications of recombination for HIV diversity. Virus Res 134:64–73PubMedCrossRefGoogle Scholar
  116. Rezende LF, Drosopoulos WC, Prasad VR (1998a) The influence of 3TC resistance mutation M184I on the fidelity and error specificity of human immunodeficiency virus type 1 reverse transcriptase. Nucleic Acids Res 26:3066–3072PubMedCrossRefGoogle Scholar
  117. Rezende LF, Curr K, Ueno T, Mitsuya H, Prasad VR (1998b) The impact of multidideoxynucleoside resistance-conferring mutations in human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and error specificity. J Virol 72:2890–2895PubMedGoogle Scholar
  118. Ricchetti M, Buc H (1990) Reverse transcriptases and genomic variability: the accuracy of DNA replication is enzyme specific and sequence dependent. EMBO J 9:1583–1593PubMedGoogle Scholar
  119. Roberts JD, Bebenek K, Kunkel TA (1988) The accuracy of reverse transcriptase from HIV-1. Science 242:1171–1173PubMedCrossRefGoogle Scholar
  120. Roberts JD, Preston BD, Johnston LA, Soni A, Loeb LA, Kunkel TA (1989) Fidelity of two retroviral reverse transcriptases during DNA-dependent DNA synthesis in vitro. Mol Cell Biol 9:469–476PubMedGoogle Scholar
  121. Rous P, Murphy JB (1913) Variations in a chicken sarcoma caused by a filterable agent. J Exp Med 17:219–231PubMedCrossRefGoogle Scholar
  122. Sadler HA, Stenglein MD, Harris RS, Mansky LM (2010) APOBEC3G contributes to HIV-1 variation through sublethal mutagenesis. J Virol 84:7396–7404PubMedCrossRefGoogle Scholar
  123. Sala M, Wain-Hobson S, Schaeffer F (1995) Human immunodeficiency virus type 1 reverse transcriptase tG:T mispair formation on RNA and DNA templates with mismatched primers: a kinetic and thermodynamic study. EMBO J 14:4622–4627PubMedGoogle Scholar
  124. Sanjuán R, Nebot MR, Chirico N, Mansky LM, Belshaw R (2010) Viral mutation rates. J Virol 84:9733–9748PubMedCrossRefGoogle Scholar
  125. 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 20:1449–1461PubMedCrossRefGoogle Scholar
  126. Shah FS, Curr KA, Hamburgh ME, Parniak M, Mitsuya H, Arnez JG, Prasad VR (2000) Differential influence of nucleoside analog-resistance mutations K65R and L74V on the overall mutation rate and error specificity of human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem 275:27037–27044PubMedGoogle Scholar
  127. Sharma PL, Nettles JH, Feldman A, Rapp K, Schinazi RF (2009) Comparative analysis of in vitro processivity of HIV-1 reverse transcriptases containing mutations 65R, 74V, 184V and 65R + 74V. Antiviral Res 83:317–323PubMedCrossRefGoogle Scholar
  128. Skasko M, Weiss KK, Reynolds HM, Jamburuthugoda V, Lee K, Kim B (2005) Mechanistic differences in RNA-dependent DNA polymerization and fidelity between murine leukemia virus and HIV-1 reverse transcriptases. J Biol Chem 280:12190–12200PubMedCrossRefGoogle Scholar
  129. Stuke AW, Ahmad-Omar O, Hoefer K, Hunsmann G, Jentsch KD (1997) Mutations in the SIV env and the M13 lacZα gene generated in vitro by reverse transcriptases and DNA polymerases. Arch Virol 142:1139–1154PubMedCrossRefGoogle Scholar
  130. Svarovskaia ES, Cheslock SR, Zhang W-H, Hu W-S, Pathak VK (2003) Retroviral mutation rates and reverse transcriptase fidelity. Front Biosci 8:D117–D134PubMedCrossRefGoogle Scholar
  131. Tamura K, Nei M, Kumar S (2004) Prospects for inferring very large phylogenies by using the neighbor-joining method. Proc Natl Acad Sci USA 101:11030–11035PubMedCrossRefGoogle Scholar
  132. Tamura K, Dudley J, Nei M, Kumar S (2007) MEGA4: molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol Biol Evol 24:1596–1599PubMedCrossRefGoogle Scholar
  133. Temin H (1960) The control of cellular morphology in embryonic cells infected with Rous sarcoma virus in vitro. Virology 10:182–197PubMedCrossRefGoogle Scholar
  134. Temin HM, Mizutani S (1970) RNA-dependent DNA polymerase in virions of Rous sarcoma virus. Nature 226:1211–1213PubMedCrossRefGoogle Scholar
  135. Varela-Echavarría A, Garvey N, Preston BD, Dougherty JP (1992) Comparison of Moloney murine leukemia virus mutation rate with the fidelity of its reverse transcriptase in vitro. J Biol Chem 267:24681–24688PubMedGoogle Scholar
  136. Vartanian JP, Sommer P, Wain-Hobson S (2003) Death and the retrovirus. Trends Mol Med 9:409–413PubMedCrossRefGoogle Scholar
  137. Vignuzzi M, Stone JK, Arnold JJ, Cameron CE, Andino R (2006) Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature 439:344–348PubMedCrossRefGoogle Scholar
  138. Vignuzzi M, Wendt E, Andino R (2008) Engineering attenuated virus vaccines by controlling replication fidelity. Nat Med 14:154–161PubMedCrossRefGoogle Scholar
  139. Wainberg MA, Drosopoulos WC, Salomon H, Hsu M, Borkow G, Parniak MA, Gu Z, Song Q, Manne J, Islam S, Castriota G, Prasad VR (1996) Enhanced fidelity of 3TC-selected mutant HIV-1 reverse transcriptase. Science 271:1282–1285PubMedCrossRefGoogle Scholar
  140. Weiss KK, Isaacs SJ, Tran NH, Adman ET, Kim B (2000) Molecular architecture of the mutagenic active site of human immunodeficiency virus type 1 reverse transcriptase: roles of the β8-αE loop in fidelity, processivity, and substrate interactions. Biochemistry 39:10684–10694PubMedCrossRefGoogle Scholar
  141. Weiss KK, Bambara RA, Kim B (2002) Mechanistic role of residue Gln151 in error prone DNA synthesis by human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) – pre-steady state kinetic study of the Q151N HIV-1 RT mutant with increased fidelity. J Biol Chem 277:22662–22669PubMedCrossRefGoogle Scholar
  142. Weiss KK, Chen R, Skasko M, Reynolds HM, Lee K, Bambara RA, Mansky LM, Kim B (2004) A role for dNTP binding of human immunodeficiency virus type 1 reverse transcriptase in viral mutagenesis. Biochemistry 43:4490–4500PubMedCrossRefGoogle Scholar
  143. Weymouth LA, Loeb LA (1978) Mutagenesis during in vitro DNA synthesis. Proc Natl Acad Sci USA 75:1924–1928PubMedCrossRefGoogle Scholar
  144. Wisniewski M, Palaniappan C, Fu Z, Le Grice SFJ, Fay P, Bambara RA (1999) Mutations in the primer grip region of HIV reverse transcriptase can increase replication fidelity. J Biol Chem 274:28175–28184PubMedCrossRefGoogle Scholar
  145. Xu H-T, Quan Y, Asahchop E, Oliveira M, Moisi D, Wainberg MA (2010) Comparative biochemical analysis of recombinant reverse transcriptase enzymes of HIV-1 subtype B and subtype C. Retrovirology 7:80PubMedCrossRefGoogle Scholar
  146. Yasukawa K, Nemoto D, Inouye K (2008) Comparison of the thermal stabilities of reverse transcriptases from avian myeloblastosis virus and Moloney murine leukaemia virus. J Biochem 143:261–268PubMedCrossRefGoogle Scholar
  147. Yu H, Goodman MF (1992) Comparison of HIV-1 and avian myeloblastosis virus reverse transcriptase fidelity on RNA and DNA templates. J Biol Chem 267:10888–10896PubMedGoogle Scholar
  148. Yu H, Jetzt AE, Dougherty JP (1997) Use of single-cycle analysis to study rates and mechanisms of retroviral mutation. Methods 12:325–336PubMedCrossRefGoogle Scholar
  149. Zhang W-H, Svarovskaia ES, Barr R, Pathak VK (2002a) Y586F mutation in murine leukemia virus reverse transcriptase decreases fidelity of DNA synthesis in regions associated with adenine-thymine tracts. Proc Natl Acad Sci USA 99:10090–10095PubMedCrossRefGoogle Scholar
  150. Zhang W-H, Hwang CK, Hu W-S, Gorelick RJ, Pathak VK (2002b) Zinc finger domain of murine leukemia virus nucleocapsid protein enhances the rate of viral DNA synthesis in vivo. J Virol 76:7473–7484PubMedCrossRefGoogle Scholar
  151. Zinnen S, Hsieh J-C, Modrich P (1994) Misincorporation and mispaired primer extension by human immunodeficiency virus reverse transcriptase. J Biol Chem 269:24195–24202PubMedGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Centro de Biología Molecular “Severo Ochoa” (Consejo Superior de Investigaciones Científicas & Universidad Autónoma de Madrid)MadridSpain

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