Hiv-1 polymerase inhibition by nucleoside analogs: Cellular- and kinetic parameters of efficacy, susceptibility and resistance selection

PLoS Computational Biology

Volumn 8, Issue 1, 2012, Pages

  von Kleist, Max ^a   Metzner, Philipp ^b   Marquet, Roland ^c   Schütte, Christof ^a  

^a FREIE UNIVERSITÄT BERLIN   (Germany)

^b UNIVERSITY OF LUGANO   (Switzerland)

^c UNIVERSITÉ DE STRASBOURG   (France)

Author keywords

[No Author keywords available]

Indexed keywords

BIOMOLECULES; CELLS; CYTOLOGY; DISEASES; KINETICS;

CELLULAR PARAMETERS; KINETICS PARAMETER; MECHANISM OF ACTION; NUCLEOSIDE ANALOGS; PRIMER EXTENSION; RESISTANCE MECHANISMS; REVERSE-TRANSCRIPTASE; TARGET CELLS; VIRAL FITNESS; VIRAL INFECTIONS;

VIRUSES;

ANTIVIRUS AGENT; CARBOVIR; EMTRICITABINE; EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; LAMIVUDINE; LAMIVUDINE PLUS STAVUDINE; NUCLEOSIDE ANALOG; NUCLEOTIDE; RNA DIRECTED DNA POLYMERASE; RNA DIRECTED DNA POLYMERASE INHIBITOR; STAVUDINE; TENOFOVIR; TENOFOVIR DISOPROXIL; THYMIDINE; ZIDOVUDINE; 3'-AZIDO-3'-DEOXYTHYMIDINE 5'-TRIPHOSPHATE; ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; DIDEOXYNUCLEOTIDE; DRUG DERIVATIVE; NUCLEOSIDE; POL PROTEIN; PYRIMIDINE NUCLEOTIDE; VIRUS DNA; VIRUS RNA; ZIDOVUDINE 5' TRIPHOSPHATE;

ANTIVIRAL ACTIVITY; ANTIVIRAL RESISTANCE; ANTIVIRAL SUSCEPTIBILITY; ARTICLE; BINDING AFFINITY; CELLULAR PARAMETERS; CONTROLLED STUDY; DRUG EFFICACY; DRUG PROTEIN BINDING; ENZYME INHIBITION; ENZYME KINETICS; EPISTASIS; HUMAN; HUMAN CELL; MATHEMATICAL MODEL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG ANTAGONISM; DRUG EFFECT; ENZYMOLOGY; GENETICS; HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; KINETICS; METABOLISM; MOLECULAR GENETICS; MUTATION; NUCLEOTIDE SEQUENCE; VIROLOGY;

HUMAN IMMUNODEFICIENCY VIRUS 1;

ANTI-HIV AGENTS; BASE SEQUENCE; DIDEOXYNUCLEOTIDES; DNA, VIRAL; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HIV REVERSE TRANSCRIPTASE; HIV-1; HUMANS; KINETICS; MODELS, MOLECULAR; MOLECULAR SEQUENCE DATA; MUTATION; NUCLEOSIDES; POL GENE PRODUCTS, HUMAN IMMUNODEFICIENCY VIRUS; REVERSE TRANSCRIPTASE INHIBITORS; RNA, VIRAL; THYMINE NUCLEOTIDES; ZIDOVUDINE;

EID: 84857479059     PISSN: 1553734X     EISSN: 15537358     Source Type: Journal    
DOI: 10.1371/journal.pcbi.1002359     Document Type: Article

References (77)

1. Clercq ED, (2002) Strategies in the design of antiviral drugs. Nat Rev Drug Discov 1: 925 13-25.
2. Tsai CH, Lee PY, Stollar V, Li ML, (2006) Antiviral therapy targeting viral poly-merase. Curr Pharm Des 12: 1339-1355.
3. Straus SE, Takiff HE, Seidlin M, Bachrach S, Lininger L, et al. (1984) Suppression of frequently recurring genital herpes. A placebo-controlled double-blind trial of oral acyclovir. N Engl J Med 310: 1545-1550.
4. Douglas JM, Critchlow C, Benedetti J, Mertz GJ, Connor JD, et al. (1984) A double blind study of oral acyclovir for suppression of recurrences of genital herpes simplex 3 virus infection. N Engl J Med 310: 1551-1556.
5. Fischl MA, Richman DD, Grieco MH, Gottlieb MS, Volberding PA, et al. (1987) The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317: 185-191.
6. Painter GR, Almond MR, Mao S, Liotta DC, (2004) Biochemical and mechanistic basis for the activity of nucleoside analogue inhibitors of HIV reverse transcriptase. Curr Top Med Chem 4: 1035-1044.
7. von Kleist M, Menz S, Huisinga W, (2010) Drug-class specific impact of antivirals on the reproductive capacity of HIV. PloS Comput Biol 6: e1000720.
8. Johnson AA, Ray AS, Hanes J, Suo Z, Colacino JM, et al. (2001) Toxicity of antiviral nucleoside analogs and the human mitochondrial DNA polymerase. J Biol Chem 276: 40847-40857.
9. Lewis W, Day BJ, Copeland WC, (2003) Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov 2: 812-822.
10. Brown JA, Pack LR, Fowler JD, Suo Z, (2011) Pre-steady-state kinetic analysis of the incorporation of anti-HIV nucleotide analogs catalyzed by human x- and y-family DNA polymerases. Antimicrob Agents Chemother 55: 276-283.
11. Hanes JW, Zhu Y, Parris DS, Johnson KA, (2007) Enzymatic therapeutic index of acyclovir. Viral versus human polymerase gamma specificity. J Biol Chem 282: 25159-25167.
12. Menndez-Arias L, (2008) Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res 134: 124-146.
13. Goldschmidt V, Marquet R, (2004) Primer unblocking by HIV-1 reverse transcriptase and resistance to nucleoside RT inhibitors (NRTIs). Int J Biochem Cell Biol 36: 1687-1705.
14. Goody RS, Mller B, Restle T, (1991) Factors contributing to the inhibition of HIV reverse transcriptase by chain-terminating nucleotides in vitro and in vivo. FEBS Lett 291: 1-5.
15. Meyer PR, Matsuura SE, Mian AM, So AG, Scott WA, (1999) A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell 4: 35-43.
16. 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.
17. Ray AS, Murakami E, Basavapathruni A, Vaccaro JA, Ulrich D, et al. (2003) Prob-ing the molecular mechanisms of AZT drug resistance mediated by HIV-1 reverse transcriptase using a transient kinetic analysis. Biochemistry 42: 8831-8841.
18. Krebs R, Immendrfer U, Thrall SH, Whrl BM, Goody RS, (1997) Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. Biochemistry 36: 10292-10300.
19. Khalili S, Monaco JM, Armaou A, (2010) Development of a stochastic model for the efficacy of NRTIs using known mechanisms of action. J Theor Biol 265: 704-717.
20. Buckheit RW, (2004) Understanding HIV resistance, fitness, replication capacity and compensation: targeting viral fitness as a therapeutic strategy. Expert Opin Investig Drugs 13: 933-958.
21. Martinez-Picado J, Martnez MA, (2008) HIV-1 reverse transcriptase inhibitor resis-tance mutations and fitness: a view from the clinic and ex vivo. Virus Res 134: 104-123.
22. Bonhoeffer S, Chappey C, Parkin NT, Whitcomb JM, Petropoulos CJ, (2004) Evidence for positive epistasis in hiv-1. Science 306: 1547-1550.
23. Martnez JP, Bocharov G, Ignatovich A, Reiter J, Dittmar MT, et al. (2011) Fitness ranking of individual mutants drives patterns of epistatic interactions in hiv-1. PLoS One 6: e18375.
24. D'Abramo CM, Cellai L, Gtte M, (2004) Excision of incorporated nucleotide analogue chain-terminators can diminish their inhibitory effects on viral RNA-dependent RNA polymerases. J Mol Biol 337: 1-14.
25. Deval J, Powdrill MH, D'Abramo CM, Cellai L, Gtte M, (2007) Pyrophosphorolytic excision of nonobligate chain terminators by hepatitis C virus NS5B polymerase. Antimicrob Agents Chemother 51: 2920-2928.
26. Urban S, Urban S, Fischer KP, Tyrrell DL, (2001) Efficient pyrophosphorolysis by a hepatitis b virus polymerase may be a primer-unblocking mechanism. Proc Natl Acad Sci U S A 98: 4984-4989.
27. von Kleist M, Menz S, Stocker H, Arasteh K, Schütte C, et al. (2011) HIV quasispecies dynamics during pro-active treatment switching: Impact on multi-drug resistance and resistance archiving in latent reservoirs. PloS One 6: e18204.
28. Klatzmann D, Barr-Sinoussi F, Nugeyre MT, Danquet C, Vilmer E, et al. (1984) Selective tropism of lymphadenopathy associated virus (LAV) for helper-inducer T lymphocytes. Science 225: 59-63.
29. Koenig S, Gendelman HE, Orenstein JM, Canto MCD, Pezeshkpour GH, et al. (1986) Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science 233: 1089-1093.
30. Patterson S, Rae A, Hockey N, Gilmour J, Gotch F, (2001) Plasmacytoid dendritic cells are highly susceptible to human immunodeficiency virus type 1 infection and release infectious virus. J Virol 75: 6710-6713.
31. Valentin A, Rosati M, Patenaude DJ, Hatzakis A, Kostrikis LG, et al. (2002) Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy. Proc Natl Acad Sci U S A 99: 7015-7020.
32. Takahashi K, Wesselingh SL, Griffin DE, McArthur JC, Johnson RT, et al. (1996) Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol 39: 705-711.
33. Kepler TB, Perelson AS, (1998) Drug concentration heterogeneity facilitates the evolution of drug resistance. Proc Natl Acad Sci U S A 95: 11514-11519.
34. Smith AJ, Scott WA, (2006) The influence of natural substrates and inhibitors on the nucleotide-dependent excision activity of HIV-1 reverse transcriptase in the infected cell. Curr Pharm Des 12: 1827-1841.
35. Smith AJ, Meyer PR, Asthana D, Ashman MR, Scott WA, (2005) Intracellular substrates for the primer-unblocking reaction by human immunodeficiency virus type 1 reverse transcriptase: detection and quantitation in extracts from quiescent- and activated-lymphocyte subpopulations. Antimicrob Agents Chemother 49: 1761-1769.
36. Traut TW, (1994) Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 140: 1-22.
37. Goday A, Simmonds HA, Webster DR, Levinsky RJ, Watson AR, et al. (1983) Importance of platelet-free preparations for evaluating lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes. Clin Sci (Lond) 65: 635-643.
38. Goday A, Webster DR, Simmonds HA, Levinsky RJ, Perrett D, et al. (1984) Nu1-cleotide levels in peripheral blood mononuclear cells of immunodeficient children: problems of measurement. Adv Exp Med Biol 165 Pt B: 179-182.
39. Tu X, Das K, Han Q, Bauman JD, Clark AD, et al. (2010) Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol 17: 1202-1209.
40. Stanford University (2011) HIV drug resistance database. URL http://hivdb.stanford.edu/pages/phenoSummary/Pheno.NRTI.Simple.html.
41. Frankel FA, Invernizzi CF, Oliveira M, Wainberg MA, (2007) Diminished efficiency of HIV-1 reverse transcriptase containing the K65R and M184V drug resistance muta-tions. AIDS 21: 665-675.
42. Svedhem V, Lindkvist A, Lidman K, Snnerborg A, (2002) Persistence of earlier HIV-1 drug resistance mutations at new treatment failure. J Med Virol 68: 473-478.
43. Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, et al. (2000) A novel pheno- typic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 44: 920-928.
44. Kakuda TN, (2000) Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 22: 685-708.
45. Aquaro S, Perno CF, Balestra E, Balzarini J, Cenci A, et al. (1997) Inhibition of replication of HIV in primary monocyte/macrophages by different antiviral drugs and comparative efficacy in lymphocytes. J Leukoc Biol 62: 138-143.
46. Kellam P, Boucher CA, Larder BA, (1992) Fifth mutation in human immunodefi-ciency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A 89: 1934-1938.
47. Byrnes VW, Emini EA, Schleif WA, Condra JH, Schneider CL, et al. (1994) Suscepti- bilities of human immunodeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reserve transcriptase in- hibitors. Antimicrob Agents Chemother 38: 1404-1407.
48. Garca-Lerma JG, Aung W, er Cong M, Zheng Q, Youngpairoj AS, et al. (2011) Natural substrate concentrations can modulate the prophylactic efficacy of nucleotide hiv reverse transcriptase inhibitors. J Virol 85: 6610-6617.
49. Perez-Bercoff D, Wurtzer S, Compain S, Benech H, Clavel F, (2007) Human immun- odeficiency virus type 1: resistance to nucleoside analogues and replicative capacity in primary human macrophages. J Virol 81: 4540-4550.
50. Buzon MJ, Massanella M, Llibre JM, Esteve A, Dahl V, et al. (2010) HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 16: 460-465.
51. Brennan TP, Woods JO, Sedaghat AR, Siliciano JD, Siliciano RF, et al. (2009) Anal- ysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. J Virol 83: 8470-8481.
52. Elena SF, Sol RV, Sardanys J, (2010) Simple genomes, complex interactions: epistasis in rna virus. Chaos 20: 026106.
53. von Kleist M, Huisinga W, (2009) Pharmacokinetic-pharmacodynamic relationship of NRTIs and its connection to viral escape: an example based on zidovudine. Eur J Pharm Sci 36: 532-543.
54. Lavie A, Schlichting I, Vetter IR, Konrad M, Reinstein J, et al. (1997) The bottleneck in AZT activation. Nat Med 3: 922-924.
55. Lavie A, Su Y, Ghassemi M, Novak RM, Caffrey M, et al. (2008) Restoration of the antiviral activity of 3′-azido-3′-deoxythymidine (AZT) against AZT-resistant human immunodeficiency virus by delivery of engineered thymidylate kinase to T cells. J Gen Virol 89: 1672-1679.
56. Ray AS, (2005) Intracellular interactions between nucleos(t)ide inhibitors of HIV re-verse transcriptase. AIDS Rev 7: 113-125.
57. McKee EE, Bentley AT, Hatch M, Gingerich J, Susan-Resiga D, (2004) Phosphoryla- tion of thymidine and AZT in heart mitochondria: elucidation of a novel mechanism of AZT cardiotoxicity. Cardiovasc Toxicol 4: 155-167.
58. Bradshaw PC, Li J, Samuels DC, (2005) A computational model of mitochondrial AZT metabolism. Biochem J 392: 363-373.
59. Freisz S, Bec G, Radi M, Wolff P, Crespan E, et al. (2010) Crystal structure of HIV-1 reverse transcriptase bound to a non-nucleoside inhibitor with a novel mechanism of action. Angew Chem Int Ed Engl 49: 1805-1808.
60. Radi M, Maga G, Alongi M, Angeli L, Samuele A, et al. (2009) Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants. J Med Chem 52: 840-851.
61. Jochmans D, Deval J, Kesteleyn B, Marck HV, Bettens E, et al. (2006) Indolopyri- dones inhibit human immunodeficiency virus reverse transcriptase with a novel mech- anism of action. J Virol 80: 12283-12292.
62. Liu S, Harada BT, Miller JT, Grice SFJL, Zhuang X, (2010) Initiation complex dy- namics direct the transitions between distinct phases of early hiv reverse transcription. Nat Struct Mol Biol 17: 1453-1460.
63. Liu S, Abbondanzieri EA, Rausch JW, Grice SFJL, Zhuang X, (2008) Slide into action: dynamic shuttling of hiv reverse transcriptase on nucleic acid substrates. Science 322: 1092-1097.
64. Thomas DC, Voronin YA, Nikolenko GN, Chen J, Hu WS, et al. (2007) Determination of the ex vivo rates of human immunodeficiency virus type 1 reverse transcription by using novel strand-specific amplification analysis. J Virol 81: 4798-4807.
65. Shen L, Peterson S, Sedaghat AR, McMahon MA, Callender M, et al. (2008) Dose- response curve slope sets class-specific limits on inhibitory potential of anti-HIV drugs. Nat Med 14: 762-766.
66. Shen L, Rabi SA, Sedaghat AR, Shan L, Lai J, et al. (2011) A critical subset model provides a conceptual basis for the high antiviral activity of major hiv drugs. Sci Transl Med 3: 91ra63.
67. Xia Q, Radzio J, Anderson KS, Sluis-Cremer N, (2007) Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses. Protein Sci 16: 1728-1737.
68. Sluis-Cremer N, Tachedjian G, (2008) Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res 134: 147-156.
69. Karlin S, Taylor HM, (1975) A first course in stochastic processes London Academic Press.
70. Norris JR, (1998) Markov chains Cambridge, UK Cambridge University Press.
71. Anderson PL, Zheng JH, King T, Bushman LR, Predhomme J, et al. (2007) Concen- trations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults. AIDS 21: 1849-1854.
72. Chapman EH, Kurec AS, Davey FR, (1981) Cell volumes of normal and malignant mononuclear cells. J Clin Pathol 34: 1083-1090.
73. Kiser JJ, Aquilante CL, Anderson PL, King TM, Carten ML, et al. (2008) Clinical and genetic determinants of intracellular tenofovir diphosphate concentrations in HIV- infected patients. J Acquir Immune Defic Syndr 47: 298-303.
74. Anderson PL, Kiser JJ, Gardner EM, Rower JE, Meditz A, et al. (2011) Pharma- cological considerations for tenofovir and emtricitabine to prevent HIV infection. J Antimicrob Chemother 66: 240-250.
75. Becher F, Landman R, Mboup S, Kane CNT, Canestri A, et al. (2004) Monitoring of didanosine and stavudine intracellular trisphosphorylated anabolite concentrations in HIV-infected patients. AIDS 18: 181-187.
76. Ray AS, Basavapathruni A, Anderson KS, (2002) Mechanistic studies to understand the progressive development of resistance in human immunodeficiency virus type 1 reverse transcriptase to abacavir. J Biol Chem 277: 40479-40490.
77. Ly JK, Margot NA, MacArthur HL, Hung M, Miller MD, et al. (2007) The balance between NRTI discrimination and excision drives the susceptibility of HIV-1 RT mu- tants K65R, M184V and K65R+M184V. Antivir Chem Chemother 18: 307-316.