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Antimicrobial Drug Resistance pp 503–519Cite as

Resistance Mechanisms to HIV-1 Nucleoside Reverse Transcriptase Inhibitors

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Abstract

HIV-1 reverse transcriptase (RT) is essential for viral replication and is a major target for antiretroviral therapy. There are 26 FDA-approved drugs for the treatment of HIV, 12 are designed to target RT and some are the most widely prescribed agents especially as fixed-dose combinations. By inhibiting the enzyme required for copying the viral genome, viral replication can be stopped. RT is responsible for synthesizing double-stranded DNA from the viral single-stranded RNA genome during the process of reverse transcription. It is a DNA polymerase that can use RNA or DNA as a template and it also has RNase H activity, which cleaves RNA annealed to DNA [1–3].

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References

  1. Arts EJ, Wainberg MA. Mechanisms of nucleoside analog antiviral activity and resistance during human immunodeficiency virus reverse transcription. Antimicrob Agents Chemother. 1996;40(3):527–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Harrich D, Hooker B. Mechanistic aspects of HIV-1 reverse transcription initiation. Rev Med Virol. 2002;12(1):31–45.

    Article  CAS  PubMed  Google Scholar 

  3. Coffin JM, Hughes SH, Varmus HE. Retroviral virions and genomes in retroviruses. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1997.

    Google Scholar 

  4. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA. Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science. 1992;256(5065):1783–90.

    Article  CAS  PubMed  Google Scholar 

  5. Jacobo-Molina A, Ding J, Nanni RG, Clark Jr AD, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clark P, et al. 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 U S A. 1993;90(13):6320–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse-transcriptase from HIV-1. Science. 1988;242(4882):1171–3.

    Article  CAS  PubMed  Google Scholar 

  7. Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science. 1995;267(5197):483–9.

    Article  CAS  PubMed  Google Scholar 

  8. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and Cd4 LYMPHOCYTES in HIV-1 infection. Nature. 1995;373(6510):123–6.

    Article  CAS  PubMed  Google Scholar 

  9. Hu WS, Temin HM. Retroviral recombination and reverse transcription. Science. 1990;250(4985):1227–33.

    Article  CAS  PubMed  Google Scholar 

  10. Pathak VK, Temin HM. Broad spectrum of in vivo forward mutations, hypermutations, and mutational hotspots in a retroviral shuttle vector after a single replication cycle: substitutions, frameshifts, and hypermutations. Proc Natl Acad Sci U S A. 1990;87(16):6019–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mansky LM, Temin HM. Lower in-vivo mutation-rate of human-immunodeficiency-virus type-1 than that predicted from the fidelity of purified reverse-transcriptase. J Virol. 1995;69(8):5087–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kepler TB, Perelson AS. Drug concentration heterogeneity facilitates the evolution of drug resistance. Proc Natl Acad Sci U S A. 1998;95(20):11514–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Herman BD, Sluis-Cremer N. Molecular pharmacology of nucleoside and nucleotide HIV-1 reverse transcriptase inhibitors. In: Gallelli L, editor. Pharmacology. InTech; 2012. DOI: 10.5772/32969. Available from: http://www.intechopen.com/books/pharmacology/molecular-pharmacologyof-nucleoside-and-nucleotide-hiv-1-reverse-transcriptase-inhibitors

  14. Bazzoli C, Jullien V, Le Tiec C, Rey E, Mentre F, Taburet AM. Intracellular pharmacokinetics of antiretroviral drugs in HIV-infected patients, and their correlation with drug action. Clin Pharmacokinet. 2010;49(1):17–45.

    Article  CAS  PubMed  Google Scholar 

  15. Cihlar T, Ray AS. Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 2010;85(1):39–58.

    Article  CAS  PubMed  Google Scholar 

  16. Sarafianos SG, Clark Jr AD, Das K, Tuske S, Birktoft JJ, Ilankumaran P, Ramesha AR, Sayer JM, Jerina DM, Boyer PL, Hughes SH, Arnold E. Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J. 2002;21(23):6614–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Isel C, Ehresmann C, Walter P, Ehresmann B, Marquet R. The emergence of different resistance mechanisms toward nucleoside inhibitors is explained by the properties of the wild type HIV-1 reverse transcriptase. J Biol Chem. 2001;276(52):48725–32.

    Article  CAS  PubMed  Google Scholar 

  18. Reardon JE. Human immunodeficiency virus reverse transcriptase: steady-state and pre-steady-state kinetics of nucleotide incorporation. Biochemistry. 1992;31(18):4473–9.

    Article  CAS  PubMed  Google Scholar 

  19. Sarafianos SG, Das K, Clark Jr AD, Ding J, Boyer PL, Hughes SH, Arnold E. Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids. Proc Natl Acad Sci U S A. 1999;96(18):10027–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Martin JL, Wilson JE, Haynes RL, Furman PA. Mechanism of resistance of human immunodeficiency virus type 1 to 2′,3′-dideoxyinosine. Proc Natl Acad Sci U S A. 1993;90(13):6135–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Harrigan PR, Stone C, Griffin P, Najera I, Bloor S, Kemp S, Tisdale M, Larder B. Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group. J Infect Dis. 2000;181(3):912–20.

    Article  CAS  PubMed  Google Scholar 

  22. Margot NA, Lu B, Cheng A, Miller MD, Study T. Resistance development over 144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or stavudine with lamivudine and efavirenz in Study 903. HIV Med. 2006;7(7):442–50.

    Article  CAS  PubMed  Google Scholar 

  23. Ueno T, Shirasaka T, Mitsuya H. Enzymatic characterization of human immunodeficiency virus type 1 reverse transcriptase resistant to multiple 2′,3′-dideoxynucleoside 5′-triphosphates. J Biol Chem. 1995;270(40):23605–11.

    Article  CAS  PubMed  Google Scholar 

  24. Menendez-Arias L. Mechanisms of resistance to nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Virus Res. 2008;134(1–2):124–46.

    Article  CAS  PubMed  Google Scholar 

  25. Ahluwalia G, Cooney DA, Mitsuya H, Fridland A, Flora KP, Hao Z, Dalal M, Broder S, Johns DG. Initial studies on the cellular pharmacology of 2′,3′-dideoxyinosine, an inhibitor of HIV infectivity. Biochem Pharmacol. 1987;36(22):3797–800.

    Article  CAS  PubMed  Google Scholar 

  26. Deval J, Navarro JM, Selmi B, Courcambeck J, Boretto J, Halfon P, Garrido-Urbani S, Sire J, Canard B. A loss of viral replicative capacity correlates with altered DNA polymerization kinetics by the human immunodeficiency virus reverse transcriptase bearing the K65R and L74V dideoxynucleoside resistance substitutions. J Biol Chem. 2004;279(24):25489–96.

    Article  CAS  PubMed  Google Scholar 

  27. Winters MA, Shafer RW, Jellinger RA, Mamtora G, Gingeras T, Merigan TC. Human immunodeficiency virus type 1 reverse transcriptase genotype and drug susceptibility changes in infected individuals receiving dideoxyinosine monotherapy for 1 to 2 years. Antimicrob Agents Chemother. 1997;41(4):757–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. St Clair MH, Martin JL, Tudor-Williams G, Bach MC, Vavro CL, King DM, Kellam P, Kemp SD, Larder BA. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science. 1991;253(5027):1557–9.

    Article  CAS  PubMed  Google Scholar 

  29. Sharma PL, Crumpacker CS. Attenuated replication of human immunodeficiency virus type 1 with a didanosine-selected reverse transcriptase mutation. J Virol. 1997;71(11):8846–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Shirasaka T, Kavlick MF, Ueno T, Gao WY, Kojima E, Alcaide ML, Chokekijchai S, Roy BM, Arnold E, Yarchoan R, et al. Emergence of human immunodeficiency virus type 1 variants with resistance to multiple dideoxynucleosides in patients receiving therapy with dideoxynucleosides. Proc Natl Acad Sci U S A. 1995;92(6):2398–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Deval J, Selmi B, Boretto J, Egloff MP, Guerreiro C, Sarfati S, Canard B. 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. 2002;277(44):42097–104.

    Article  CAS  PubMed  Google Scholar 

  32. Daluge SM, Good SS, Faletto MB, Miller WH, Clair MHS, Boone LR, Tisdale M, Parry NR, Reardon JE, Dornsife RE, Averett DR, Krenitsky TA. 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob Agents Chemother. 1997;41(5):1082–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Faletto MB, Miller WH, Garvey EP, Clair MHS, Daluge SM, Good SS. Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother. 1997;41(5):1099–107.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Tisdale M, Alnadaf T, Cousens D. Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89. Antimicrob Agents Chemother. 1997;41(5):1094–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Krebs R, Immendorfer U, Thrall SH, Wohrl BM, Goody RS. Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. Biochemistry. 1997;36(33):10292–300.

    Article  CAS  PubMed  Google Scholar 

  36. Feng JY, Anderson KS. Mechanistic studies examining the efficiency and fidelity of DNA synthesis by the 3TC-resistant mutant (184V) of HIV-1 reverse transcriptase. Biochemistry. 1999;38(29):9440–8.

    Article  CAS  PubMed  Google Scholar 

  37. Wilson JE, Aulabaugh A, Caligan B, McPherson S, Wakefield JK, Jablonski S, Morrow CD, Reardon JE, Furman PA. Human immunodeficiency virus type-1 reverse transcriptase. Contribution of Met-184 to binding of nucleoside 5′-triphosphate. J Biol Chem. 1996;271(23):13656–62.

    Article  CAS  PubMed  Google Scholar 

  38. De Clercq E. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents. 2009;33(4):307–20.

    Article  PubMed  CAS  Google Scholar 

  39. Yarchoan R, Perno CF, Thomas RV, Klecker RW, Allain JP, Wills RJ, McAtee N, Fischl MA, Dubinsky R, McNeely MC, et al. Phase I studies of 2′,3′-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine (AZT). Lancet. 1988;1(8577):76–81.

    Article  CAS  PubMed  Google Scholar 

  40. Chen CH, Cheng YC. Delayed cytotoxicity and selective loss of mitochondrial DNA in cells treated with the anti-human immunodeficiency virus compound 2′,3′-dideoxycytidine. J Biol Chem. 1989;264(20):11934–7.

    CAS  PubMed  Google Scholar 

  41. Roche-Pharmaceuticals. M.D./Alert. [Letter]. 2006 [cited 2012 June 10]. http://www.fda.gov/downloads/drugs/drug/safety/drugshortages/ucm086099.pdf.

  42. Lee H, Hanes J, Johnson KA. Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry. 2003;42(50):14711–9.

    Article  CAS  PubMed  Google Scholar 

  43. Schinazi RF, McMillan A, Cannon D, Mathis R, Lloyd RM, Peck A, Sommadossi JP, Clair MS, Wilson J, Furman PA, et al. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother. 1992;36(11):2423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hart GJ, Orr DC, Penn CR, Figueiredo HT, Gray NM, Boehme RE, Cameron JM. Effects of (-)-2′-deoxy-3′-thiacytidine (3TC) 5′-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma. Antimicrob Agents Chemother. 1992;36(8):1688–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Coates JA, Cammack N, Jenkinson HJ, Mutton IM, Pearson BA, Storer R, Cameron JM, Penn CR. The separated enantiomers of 2′-deoxy-3′-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob Agents Chemother. 1992;36(1):202–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gao Q, Gu Z, Parniak MA, Cameron J, Cammack N, Boucher C, Wainberg MA. The same mutation that encodes low-level human immunodeficiency virus type 1 resistance to 2′,3′-dideoxyinosine and 2′,3′-dideoxycytidine confers high-level resistance to the (-)enantiomer of 2′,3′-dideoxy-3′-thiacytidine. Antimicrob Agents Chemother. 1993;37(6):1390–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schinazi RF, Lloyd Jr RM, Nguyen MH, Cannon DL, McMillan A, Ilksoy N, Chu CK, Liotta DC, Bazmi HZ, Mellors JW. Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother. 1993;37(4):875–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kavlick MF, Shirasaka T, Kojima E, Pluda JM, Hui Jr F, Yarchoan R, Mitsuya H. Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (--)-2′,3′-dideoxy-3′-thiacytidine. Antiviral Res. 1995;28(2):133–46.

    Article  CAS  PubMed  Google Scholar 

  49. Svicher V, Alteri C, Artese A, Forbici F, Santoro MM, Schols D, Van Laethem K, Alcaro S, Costa G, Tommasi C, Zaccarelli M, Narciso P, Antinori A, Ceccherini-Silberstein F, Balzarini J, Perno CF. Different evolution of genotypic resistance profiles to emtricitabine versus lamivudine in tenofovir-containing regimens. J Acquir Immune Defic Syndr. 2010;55(3):336–44.

    Article  CAS  PubMed  Google Scholar 

  50. Gutfreund K, Williams M, George R, Bain V, Ma M, Yoshida E, Villeneuve J, Fischer K, Tyrrel D. Genotypic succession of mutations of the hepatitis B virus polymerase associated with lamivudine resistance. J Hepatol. 2000;33(3):469–75.

    Article  CAS  PubMed  Google Scholar 

  51. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, DeHertogh D, Wilber R, Zink RC, Cross A, Colonno R, Fernandes L, Group BEAS. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354(10):1011–20.

    Article  CAS  PubMed  Google Scholar 

  52. Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, Boron-Kaczmarska A, Martin P, Goodman Z, Colonno R, Cross A, Denisky G, Kreter B, Hindes R, Group AIBS. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130(7):2039–49.

    Article  CAS  PubMed  Google Scholar 

  53. mcMahon M, Jilek B, Brennan T, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hergarty R, Chong C, Liu J, Siliciano R, Thio C. The HBV drug entecavir—effects on HIV-1 replication and resistance. N Engl J Med. 2007;356(25):2614–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Domaoal RA, McMahon M, Thio CL, Bailey CM, Tirado-Rives J, Obikhod A, Detorio M, Rapp KL, Siliciano RF, Schinazi RF, Anderson KS. Pre-steady-state kinetic studies establish entecavir 5′-triphosphate as a substrate for HIV-1 reverse transcriptase. J Biol Chem. 2008;283(9):5452–9.

    Article  CAS  PubMed  Google Scholar 

  55. Tchesnokov EP, Obikhod A, Schinazi RF, Gotte M. Delayed chain termination protects the anti-hepatitis B virus drug entecavir from excision by HIV-1 reverse transcriptase. J Biol Chem. 2008;283(49):34218–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Langley DR, Walsh AW, Baldick CJ, Eggers BJ, Rose RE, Levine SM, Kapur AJ, Colonno RJ, Tenney DJ. Inhibition of hepatitis B virus polymerase by entecavir. J Virol. 2007;81(8):3992–4001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. De Clercq E. The acyclic nucleoside phosphonates from inception to clinical use: historical perspective. Antiviral Res. 2007;75(1):1–13.

    Article  PubMed  CAS  Google Scholar 

  58. Naesens L, Bischofberger N, Augustijns P, Annaert P, Van den Mooter G, Arimilli MN, Kim CU, De Clercq E. Antiretroviral efficacy and pharmacokinetics of oral bis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine in mice. Antimicrob Agents Chemother. 1998;42(7):1568–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Robbins BL, Srinivas RV, Kim C, Bischofberger N, Fridland A. Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother. 1998;42(3):612–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wainberg MA, Miller MD, Quan Y, Salomon H, Mulato AS, Lamy PD, Margot NA, Anton KE, Cherrington JM. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antivir Ther. 1999;4(2):87–94.

    CAS  PubMed  Google Scholar 

  61. Margot NA, Waters JM, Miller MD. In vitro human immunodeficiency virus type 1 resistance selections with combinations of tenofovir and emtricitabine or abacavir and lamivudine. Antimicrob Agents Chemother. 2006;50(12):4087–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. McColl D, Margot N, Wulfsohn M, Coakley D, Cheng A, Miller MD. Patterns of resistance emerging in HIV-1 from antiretroviral-experienced patients undergoing intensification therapy with tenofovir disoproxil fumarate. J Acquir Immune Defic Syndr. 2004;37(3):1340–50.

    Article  CAS  PubMed  Google Scholar 

  63. Ross L, Gerondelis P, Liao Q, Wine B, Lim M, Shaefer M, Rodriguez A, Limoli K, Huang W, Parkin NT, Gallant J, Lanier R. Selection of the HIV-1 reverse transcriptase mutation K70E in antiretroviral-naive subjects treated with tenofovir/abacavir/lamivudine therapy (abstract no. 92). In: 14th international HIV drug resistance workshop. 2005. Québec City, Canada.

    Google Scholar 

  64. Kagan RM, Lee TS, Ross L, Lloyd Jr RM, Lewinski MA, Potts SJ. Molecular basis of antagonism between K70E and K65R tenofovir-associated mutations in HIV-1 reverse transcriptase. Antiviral Res. 2007;75(3):210–8.

    Article  CAS  PubMed  Google Scholar 

  65. Parikh UM, Koontz DL, Chu CK, Schinazi RF, Mellors JW. In vitro activity of structurally diverse nucleoside analogs against human immunodeficiency virus type 1 with the K65R mutation in reverse transcriptase. Antimicrob Agents Chemother. 2005;49(3):1139–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Skhosana L, Steegen K, Bronze M, Lukhwareni A, Letsoalo E, Papathanasopoulos MA, Carmona SC, Stevens WS. High prevalence of the K65R mutation in HIV-1 subtype C infected patients failing tenofovir-based first-line regimens in South Africa. PLoS One. 2015;10(2):e0118145.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Sluis-Cremer N, Arion D, Kaushik N, Lim H, Parniak MA. Mutational analysis of Lys65 of HIV-1 reverse transcriptase. Biochem J. 2000;348(Pt 1):77–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Parikh UM, Zelina S, Sluis-Cremer N, Mellors JW. Molecular mechanisms of bidirectional antagonism between K65R and thymidine analog mutations in HIV-1 reverse transcriptase. AIDS. 2007;21(11):1405–14.

    Article  CAS  PubMed  Google Scholar 

  69. Parikh UM, Bacheler L, Koontz D, Mellors JW. The K65R mutation in human immunodeficiency virus type 1 reverse transcriptase exhibits bidirectional phenotypic antagonism with thymidine analog mutations. J Virol. 2006;80(10):4971–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sluis-Cremer N, Sheen CW, Zelina S, Torres PS, Parikh UM, Mellors JW. Molecular mechanism by which the K70E mutation in human immunodeficiency virus type 1 reverse transcriptase confers resistance to nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2007;51(1):48–53.

    Article  CAS  PubMed  Google Scholar 

  71. Ruane P, DeJesus E, Berger D, Markowitz M, Bredeek U, Callebaut C, Zhong L, Ramanathan S, Rhee M, Fordyce M, Yale K. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63(4):449–55.

    Article  CAS  PubMed  Google Scholar 

  72. Margot NA, Johnson A, Miller MD, Callebaut C. Characterization of HIV-1 resistance to tenofovir alafenamide in vitro. Antimicrob Agents Chemother. 2015;59(10):5917–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sax P, Wohl D, Yin M, Post F, DeJesus E, Saag M, Pozniak A, Thompson M, Podzamczer D, Molina J, Oka S, Koenig E, Trottier B, Andrade-Villanueva J, Crofoot G, Custodio J, Plummer A, Zhong L, Cao H, Martin H, Callebaut C, Cheng A, Fordyce M, McCallister S, GS-US Team. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet 2015;385(9987): 2606–15.

    Google Scholar 

  74. Takamatsu Y, Tanaka Y, Kohgo S, Murakami S, Singh K, Das D, Venzon DJ, Amano M, Higashi-Kuwata N, Aoki M, Delino NS, Hayashi S, Takahashi S, Sukenaga Y, Haraguchi K, Sarafianos SG, Maeda K, Mitsuya H. 4′-Modified nucleoside analogs: potent inhibitors active against entecavir-resistant hepatitis B virus. Hepatology. 2015;62(4):1024–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kawamoto A, Kodama E, Sarafianos SG, Sakagami Y, Kohgo S, Kitano K, Ashida N, Iwai Y, Hayakawa H, Nakata H, Mitsuya H, Arnold E, Matsuoka M. 2′-Deoxy-4′-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants. Int J Biochem Cell Biol. 2008;40(11):2410–20.

    Article  CAS  PubMed  Google Scholar 

  76. Kodama EI, Kohgo S, Kitano K, Machida H, Gatanaga H, Shigeta S, Matsuoka M, Ohrui H, Mitsuya H. 4′-Ethynyl nucleoside analogs: potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro. Antimicrob Agents Chemother. 2001;45(5):1539–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Michailidis E, Huber AD, Ryan EM, Ong YT, Leslie MD, Matzek KB, Singh K, Marchand B, Hagedorn AN, Kirby KA, Rohan LC, Kodama EN, Mitsuya H, Parniak MA, Sarafianos SG. 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. J Biol Chem. 2014;289(35):24533–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Michailidis E, Ryan EM, Hachiya A, Kirby KA, Marchand B, Leslie MD, Huber AD, Ong YT, Jackson JC, Singh K, Kodama EN, Mitsuya H, Parniak MA, Sarafianos SG. Hypersusceptibility mechanism of tenofovir-resistant HIV to EFdA. Retrovirology. 2013;10:65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Murphey-Corb M, Rajakumar P, Michael H, Nyaundi J, Didier PJ, Reeve AB, Mitsuya H, Sarafianos SG, Parniak MA. Response of simian immunodeficiency virus to the novel nucleoside reverse transcriptase inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine in vitro and in vivo. Antimicrob Agents Chemother. 2012;56(9):4707–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Maeda K, Desai DV, Aoki M, Nakata H, Kodama EN, Mitsuya H. Delayed emergence of HIV-1 variants resistant to 4′-ethynyl-2-fluoro-2′-deoxyadenosine: comparative sequential passage study with lamivudine, tenofovir, emtricitabine and BMS-986001. Antivir Ther. 2014;19(2):179–89.

    Article  CAS  PubMed  Google Scholar 

  81. Kim HO, Schinazi RF, Shanmuganathan K, Jeong LS, Beach JW, Nampalli S, Cannon DL, Chu CK. L-beta-(2S,4S)- and L-alpha-(2S,4R)-dioxolanyl nucleosides as potential anti-HIV agents: asymmetric synthesis and structure-activity relationships. J Med Chem. 1993;36(5):519–28.

    Article  CAS  PubMed  Google Scholar 

  82. Chen H, Boudinot F, Chu C, Mcclure H, Schinazi R. Pharmacokinetics of (-)-beta-D-2-aminopurine dioxolane and (-)-beta-D-2-amino-6-chloropurine dioxolane and their antiviral metabolite (-)-beta-D-dioxolane guanine in rhesus monkeys. Antimicrob Agents Chemother. 1996;40(10):2332–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Gu Z, Wainberg M, Nguyen-Ba N, L’Heureux L, de Muys J, Bowlin T, Rando R. Mechanism of action and in vitro activity of 1′,3′-dioxolanylpurine nucleoside analogues against sensitive and drug-resistant human immunodeficiency virus type 1 variants. Antimicrob Agents Chemother. 1999;43(10):2376–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Gu Z, Wainberg M, Nguyen-Ba P, L’Heureux L, de Muys J, Rando R. Anti-HIV-1 activities of 1,3-dioxolane guanine and 2,6-diaminopurine dioxolane. Nucleosides Nucleotides Nucleic Acids. 1999;18(4–5):891–2.

    Article  CAS  Google Scholar 

  85. Mewshaw JP, Myrick FT, Wakefield DA, Hooper BJ, Harris JL, McCreedy B, Borroto-Esoda K. Dioxolane guanosine, the active form of the prodrug diaminopurine dioxolane, is a potent inhibitor of drug-resistant HIV-1 isolates from patients for whom standard nucleoside therapy fails. J Acquir Immune Defic Syndr. 2002;29(1):11–20.

    Article  CAS  PubMed  Google Scholar 

  86. Bazmi HZ, Hammond JL, Cavalcanti SC, Chu CK, Schinazi RF, Mellors JW. In vitro selection of mutations in the human immunodeficiency virus type 1 reverse transcriptase that decrease susceptibility to (-)-beta-D-dioxolane-guanosine and suppress resistance to 3′-azido-3′-deoxythymidine. Antimicrob Agents Chemother. 2000;44(7):1783–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jeffrey JL, Feng JY, Qi CC, Anderson KS, Furman PA. Dioxolane guanosine 5′-triphosphate, an alternative substrate inhibitor of wild-type and mutant HIV-1 reverse transcriptase. Steady state and pre-steady state kinetic analyses. J Biol Chem. 2003;278(21):18971–9.

    Article  CAS  PubMed  Google Scholar 

  88. Meyer PR, Matsuura SE, So AG, Scott WA. Unblocking of chain-terminated primer by HIV-1 reverse transcriptase through a nucleotide-dependent mechanism. Proc Natl Acad Sci U S A. 1998;95(23):13471–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Arion D, Kaushik N, McCormick S, Borkow G, Parniak MA. Phenotypic mechanism of HIV-1 resistance to 3′-azido-3′-deoxythymidine (AZT): increased polymerization processivity and enhanced sensitivity to pyrophosphate of the mutant viral reverse transcriptase. Biochemistry. 1998;37(45):15908–17.

    Article  CAS  PubMed  Google Scholar 

  90. Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science. 1989;243(4899):1731–4.

    Article  CAS  PubMed  Google Scholar 

  91. Hooker DJ, Tachedjian G, Solomon AE, Gurusinghe AD, Land S, Birch C, Anderson JL, Roy BM, Arnold E, Deacon NJ. An in vivo mutation from leucine to tryptophan at position 210 in human immunodeficiency virus type 1 reverse transcriptase contributes to high-level resistance to 3′-azido-3′-deoxythymidine. J Virol. 1996;70(11):8010–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Kellam P, Boucher CA, Larder BA. Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. Proc Natl Acad Sci U S A. 1992;89(5):1934–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Harrigan PR, Kinghorn I, Bloor S, Kemp SD, Najera I, Kohli A, Larder BA. Significance of amino acid variation at human immunodeficiency virus type 1 reverse transcriptase residue 210 for zidovudine susceptibility. J Virol. 1996;70(9):5930–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Mitsuya H, Weinhold KJ, Furman PA, Clair MHS, Lehrman SN, Gallo RC, Bolognesi D, Barry DW, Broder S. 3′-Azido-3′-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985;82(20):7096–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Furman PA, Fyfe JA, Clair MHS, Weinhold K, Rideout JL, Freeman GA, Lehrman SN, Bolognesi DP, Broder S, Mitsuya H, et al. Phosphorylation of 3′-azido-3′-deoxythymidine and selective interaction of the 5′-triphosphate with human immunodeficiency virus reverse transcriptase. Proc Natl Acad Sci U S A. 1986;83(21):8333–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Anderson PL, Kakuda TN, Kawle S, Fletcher CV. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV infected individuals. AIDS. 2003;17(15):2159–68.

    Article  CAS  PubMed  Google Scholar 

  97. Department of Health and Human Services. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2015. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.

  98. Fletcher CV, Anderson PL, Kakuda TN, Schacker TW, Henry K, Gross CR, Brundage RC. Concentration-controlled compared with conventional antiretroviral therapy for HIV infection. AIDS. 2002;16(4):551–60.

    Article  PubMed  Google Scholar 

  99. Sidtis JJ, Gatsonis C, Price RW, Singer EJ, Collier AC, Richman DD, Hirsch MS, Schaerf FW, Fischl MA, Kieburtz K, Simpson D, Koch MA, Feinberg J, Dafni U. Zidovudine treatment of the AIDS dementia complex—results of a placebo-controlled trial. Ann Neurol. 1993;33(4):343–9.

    Article  CAS  PubMed  Google Scholar 

  100. Hurwitz SJ, Schinazi RF. In silico study supports the efficacy of a reduced dose regimen for stavudine. Antiviral Res. 2011;92(2):372–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Broder S. The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic. Antiviral Res. 2010;85(1):1–18.

    Article  CAS  PubMed  Google Scholar 

  102. Ray AS, Murakami E, Basavapathruni A, Vaccaro JA, Ulrich D, Chu CK, Schinazi RF, Anderson KS. Probing the molecular mechanisms of AZT drug resistance mediated by HIV-1 reverse transcriptase using a transient kinetic analysis. Biochemistry. 2003;42(29):8831–41.

    Article  CAS  PubMed  Google Scholar 

  103. Rigourd M, Ehresmann C, Parniak MA, Ehresmann B, Marquet R. Primer unblocking and rescue of DNA synthesis by azidothymidine (AZT)-resistant HIV-1 reverse transcriptase—comparison between initiation and elongation of reverse transcription and between (−) and (+) strand DNA synthesis. J Biol Chem. 2002;277(21):18611–8.

    Article  CAS  PubMed  Google Scholar 

  104. Meyer PR, Matsuura SE, Mian AM, So AG, Scott WA. A mechanism of AZT resistance: an increase in nucleotide-dependent primer unblocking by mutant HIV-1 reverse transcriptase. Mol Cell. 1999;4(1):35–43.

    Article  CAS  PubMed  Google Scholar 

  105. Boyer PL, Sarafianos SG, Arnold E, Hughes SH. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J Virol. 2001;75(10):4832–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tu XY, Das K, Han QW, Bauman JD, Clark AD, Hou XR, Frenkel YV, Gaffney BL, Jones RA, Boyer PL, Hughes SH, Sarafianos SG, Arnold E. Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol. 2010;17(10):1202–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Das K, Arnold E. HIV-1 reverse transcriptase and antiviral drug resistance. Part 2. Curr Opin Virol. 2013;3(2):119–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Jiang LJ, Maret W, Vallee BL. The ATP-metallothionein complex. Proc Natl Acad Sci U S A. 1998;95(16):9146–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kennedy EM, Gavegnano C, Nguyen L, Slater R, Lucas A, Fromentin E, Schinazi RF, Kim B. Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. J Biol Chem. 2010;285(50):39380–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Boyer PL, Gao HQ, Clark PK, Sarafianos SG, Arnold E, Hughes SH. YADD mutants of human immunodeficiency virus type 1 and Moloney murine leukemia virus reverse transcriptase are resistant to lamivudine triphosphate (3TCTP) in vitro. J Virol. 2001;75(14):6321–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tong W, Lu CD, Sharma SK, Matsuura S, So AG, Scott WA. Nucleotide-induced stable complex formation by HIV-1 reverse transcriptase. Biochemistry. 1997;36(19):5749–57.

    Article  CAS  PubMed  Google Scholar 

  112. Boyer PL, Sarafianos SG, Arnold E, Hughes SH. Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision. J Virol. 2002;76(18):9143–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Marchand B, Gotte M. Site-specific footprinting reveals differences in the translocation status of HIV-1 reverse transcriptase. Implications for polymerase translocation and drug resistance. J Biol Chem. 2003;278(37):35362–72.

    Article  CAS  PubMed  Google Scholar 

  114. Naeger LK, Margot NA, Miller MD. ATP-dependent removal of nucleoside reverse transcriptase inhibitors by human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 2002;46(7):2179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Harrigan PR, Bloor S, Larder BA. Relative replicative fitness of zidovudine-resistant human immunodeficiency virus type 1 isolates in vitro. J Virol. 1998;72(5):3773–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Hu Z, Giguel F, Hatano H, Reid P, Lu J, Kuritzkes DR. Fitness comparison of thymidine analog resistance pathways in human immunodeficiency virus type 1. J Virol. 2006;80(14):7020–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Miller MD, Margot N, Lu B, Zhong LJ, Chen SS, Cheng A, Wulfsohn M. Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J Infect Dis. 2004;189(5):837–46.

    Article  CAS  PubMed  Google Scholar 

  118. Cozzi-Lepri A, Ruiz L, Loveday C, Phillips AN, Clotet B, Reiss P, Ledergerber B, Holkmann C, Staszewski S, Lundgren JD. Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy. Antivir Ther. 2005;10(7):791–802.

    CAS  PubMed  Google Scholar 

  119. De Luca A, Di Giambenedetto S, Romano L, Gonnelli A, Corsi P, Baldari M, Di Pietro M, Menzo S, Francisci D, Almi P, Zazzi M, Cohort AR. Frequency and treatment-related predictors of thymidine-analogue mutation patterns in HIV-1 isolates after unsuccessful antiretroviral therapy. J Infect Dis. 2006;193(9):1219–22.

    Article  PubMed  Google Scholar 

  120. Yahi N, Tamalet C, Tourres C, Tivoli N, Fantini J. Mutation L210W of HIV-1 reverse transcriptase in patients receiving combination therapy—Incidence, association with other mutations, and effects on the structure of mutated reverse transcriptase. J Biomed Sci. 2000;7(6):507–13.

    Article  CAS  PubMed  Google Scholar 

  121. Rhee SY, Liu T, Ravela J, Gonzales MJ, Shafer RW. Distribution of human immunodeficiency virus type 1 protease and reverse transcriptase mutation patterns in 4,183 persons undergoing genotypic resistance testing. Antimicrob Agents Chemother. 2004;48(8):3122–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Matamoros T, Franco S, Vazquez-Alvarez BM, Mas A, Martinez MA, Menendez-Arias L. Molecular determinants of multi-nucleoside analogue resistance in HIV-1 reverse transcriptases containing a dipeptide insertion in the fingers subdomain: effect of mutations D67N and T215Y on removal of thymidine nucleotide analogues from blocked DNA primers. J Biol Chem. 2004;279(23):24569–77.

    Article  CAS  PubMed  Google Scholar 

  123. Mas A, Parera M, Briones C, Soriano V, Martinez MA, Domingo E, Menendez-Arias L. Role of a dipeptide insertion between codons 69 and 70 of HIV-1 reverse transcriptase in the mechanism of AZT resistance. EMBO J. 2000;19(21):5752–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Meyer PR, Lennerstrand J, Matsuura SE, Larder BA, Scott WA. Effects of dipeptide insertions between codons 69 and 70 of human immunodeficiency virus type 1 reverse transcriptase on primer unblocking, deoxynucleoside triphosphate inhibition, and DNA chain elongation. J Virol. 2003;77(6):3871–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. White KL, Chen JM, Margot NA, Wrin T, Petropoulos CJ, Naeger LK, Swaminathan S, Miller MD. Molecular mechanisms of tenofovir resistance conferred by human immunodeficiency virus type 1 reverse transcriptase containing a diserine insertion after residue 69 and multiple thymidine analog-associated mutations. Antimicrob Agents Chemother. 2004;48(3):992–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Imamichi T, Berg SC, Imamichi H, Lopez JC, Metcalf JA, Falloon J, Lane HC. Relative replication fitness of a high-level 3′-azido-3′-deoxythymidine-resistant variant of human immunodeficiency virus type 1 possessing an amino acid deletion at codon 67 and a novel substitution (Thr → Gly) at codon 69. J Virol. 2000;74(23):10958–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Boyer PL, Imamichi T, Sarafianos SG, Arnold E, Hughes SH. Effects of the Delta67 complex of mutations in human immunodeficiency virus type 1 reverse transcriptase on nucleoside analog excision. J Virol. 2004;78(18):9987–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ehteshami M, Gotte M. Effects of mutations in the connection and RNase H domains of HIV-1 reverse transcriptase on drug susceptibility. AIDS Rev. 2008;10(4):224–35.

    PubMed  Google Scholar 

  129. Delviks-Frankenberry KA, Nikolenko GN, Pathak VK. The “connection” between HIV drug resistance and RNase H. Viruses. 2010;2(7):1476–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Hachiya A, Kodama EN, Sarafianos SG, Schuckmann MM, Sakagami Y, Matsuoka M, Takiguchi M, Gatanaga H, Oka S. 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. 2008;82(7):3261–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Yap SH, Sheen CW, Fahey J, Zanin M, Tyssen D, Lima VD, Wynhoven B, Kuiper M, Sluis-Cremer N, Harrigan PR, Tachedjian G. N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance. PLoS Med. 2007;4(12):e335.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Menendez-Arias L, Betancor G, Matamoros T. HIV-1 reverse transcriptase connection subdomain mutations involved in resistance to approved non-nucleoside inhibitors. Antiviral Res. 2011;92(2):139–49.

    Article  CAS  PubMed  Google Scholar 

  133. Cane PA, Green H, Fearnhill E, Dunn D. Identification of accessory mutations associated with high-level resistance in HIV-1 reverse transcriptase. AIDS. 2007;21(4):447–55.

    Article  CAS  PubMed  Google Scholar 

  134. von Wyl V, Ehteshami M, Demeter LM, Burgisser P, Nijhuis M, Symons J, Yerly S, Boni J, Klimkait T, Schuurman R, Ledergerber B, Gotte M, Gunthard HF. HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy. Clin Infect Dis. 2010;51(5):620–8.

    Article  CAS  Google Scholar 

  135. Waters JM, O’Neal W, White KL, Wakeford C, Lansdon EB, Harris J, Svarovskaia ES, Miller MD, Borroto-Esoda K. Mutations in the thumb-connection and RNase H domain of HIV type-1 reverse transcriptase of antiretroviral treatment-experienced patients. Antivir Ther. 2009;14(2):231–9.

    CAS  PubMed  Google Scholar 

  136. Santos AF, Lengruber RB, Soares EA, Jere A, Sprinz E, Martinez AM, Silveira J, Sion FS, Pathak VK, Soares MA. Conservation patterns of HIV-1 RT connection and RNase H domains: identification of new mutations in NRTI-treated patients. PLoS One. 2008;3(3):e1781.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Gallego O, Corral A, de Mendoza C, Rodes B, Soriano V. Prevalence of G333D/E in naive and pretreated HIV-infected patients. AIDS Res Hum Retroviruses. 2002;18(12):857–60.

    Article  CAS  PubMed  Google Scholar 

  138. Kemp SD, Shi C, Bloor S, Harrigan PR, Mellors JW, Larder BA. A novel polymorphism at codon 333 of human immunodeficiency virus type 1 reverse transcriptase can facilitate dual resistance to zidovudine and L-2′,3′-dideoxy-3′-thiacytidine. J Virol. 1998;72(6):5093–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Zelina S, Sheen CW, Radzio J, Mellors JW, Sluis-Cremer N. Mechanisms by which the G333D mutation in human immunodeficiency virus type 1 reverse transcriptase facilitates dual resistance to zidovudine and lamivudine. Antimicrob Agents Chemother. 2008;52(1):157–63.

    Article  CAS  PubMed  Google Scholar 

  140. Lengruber RB, Delviks-Frankenberry KA, Nikolenko GN, Baumann J, Santos AF, Pathak VK, Soares MA. Phenotypic characterization of drug resistance-associated mutations in HIV-1 RT connection and RNase H domains and their correlation with thymidine analogue mutations. J Antimicrob Chemother. 2011;66(4):702–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Brehm JH, Koontz D, Meteer JD, Pathak V, Sluis-Cremer N, Mellors JW. 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. 2007;81(15):7852–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ntemgwa M, Wainberg MA, Oliveira M, Moisi D, Lalonde R, Micheli V, Brenner BG. Variations in reverse transcriptase and RNase H domain mutations in human immunodeficiency virus type 1 clinical isolates are associated with divergent phenotypic resistance to zidovudine. Antimicrob Agents Chemother. 2007;51(11):3861–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Roquebert B, Wirden M, Simon A, Deval J, Katlama C, Calvez V, Marcelin AG. Relationship between mutations in HIV-1 RNase H domain and nucleoside reverse transcriptase inhibitors resistance mutations in naive and pre-treated HIV infected patients. J Med Virol. 2007;79(3):207–11.

    Article  CAS  PubMed  Google Scholar 

  144. Delviks-Frankenberry KA, Nikolenko GN, Barr R, Pathak VK. Mutations in human immunodeficiency virus type 1 RNase H primer grip enhance 3′-azido-3′-deoxythymidine resistance. J Virol. 2007;81(13):6837–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Delviks-Frankenberry KA, Nikolenko GN, Boyer PL, Hughes SH, Coffin JM, Jere A, Pathak VK. HIV-1 reverse transcriptase connection subdomain mutations reduce template RNA degradation and enhance AZT excision. Proc Natl Acad Sci U S A. 2008;105(31):10943–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Nikolenko GN, Delviks-Frankenberry KA, Palmer S, Maldarelli F, Fivash Jr MJ, Coffin JM, Pathak VK. Mutations in the connection domain of HIV-1 reverse transcriptase increase 3′-azido-3′-deoxythymidine resistance. Proc Natl Acad Sci U S A. 2007;104(1):317–22.

    Article  CAS  PubMed  Google Scholar 

  147. Nikolenko GN, Palmer S, Maldarelli F, Mellors JW, Coffin JM, Pathak VK. Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: balance between RNase H activity and nucleotide excision. Proc Natl Acad Sci U S A. 2005;102(6):2093–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Radzio J, Sluis-Cremer N. Efavirenz accelerates HIV-1 reverse transcriptase ribonuclease H cleavage, leading to diminished zidovudine excision. Mol Pharmacol. 2008;73(2):601–6.

    Article  CAS  PubMed  Google Scholar 

  149. Ehteshami M, Beilhartz GL, Scarth BJ, Tchesnokov EP, McCormick S, Wynhoven B, Harrigan PR, Gotte M. Connection domain mutations N348I and A360V in HIV-1 reverse transcriptase enhance resistance to 3′-azido-3′-deoxythymidine through both RNase H-dependent and -independent mechanisms. J Biol Chem. 2008;283(32):22222–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Brehm JH, Lalama CM, Hughes MD, Haubrich R, Riddler SA, Sluis-Cremer N, Mellors JW, A.C.T.G.S.A.P. Team. Failure of initial therapy with two nucleosides and efavirenz is not associated with early emergence of mutations in the C-terminus of HIV-1 reverse transcriptase. J Acquir Immune Defic Syndr. 2011;56(4):344–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gupta S, Vingerhoets J, Fransen S, Tambuyzer L, Azijn H, Frantzell A, Paredes R, Coakley E, Nijs S, Clotet B, Petropoulos CJ, Schapiro J, Huang W, Picchio G. Connection domain mutations in HIV-1 reverse transcriptase do not impact etravirine susceptibility and virologic responses to etravirine-containing regimens. Antimicrob Agents Chemother. 2011;55(6):2872–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Wensing AM, Calvez V, Gunthard HF, Johnson VA, Paredes R, Pillay D, Shafer RW, Richman DD. 2014 Update of the drug resistance mutations in HIV-1. Top Antivir Med. 2014;22(3):642–50.

    PubMed  PubMed Central  Google Scholar 

  153. Dornsife RE, Clair MHS, Huang AT, Panella TJ, Koszalka GW, Burns CL, Averett DR. Anti-human immunodeficiency virus synergism by zidovudine (3′-azidothymidine) and didanosine (dideoxyinosine) contrasts with their additive inhibition of normal human marrow progenitor cells. Antimicrob Agents Chemother. 1991;35(2):322–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Yarchoan R, Lietzau JA, Nguyen BY, Brawley OW, Pluda JM, Saville MW, Wyvill KM, Steinberg SM, Agbaria R, Mitsuya H, et al. A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection. J Infect Dis. 1994;169(1):9–17.

    Article  CAS  PubMed  Google Scholar 

  155. Bridges EG, Dutschman GE, Gullen EA, Cheng YC. Favorable interaction of beta-L(-) nucleoside analogues with clinically approved anti-HIV nucleoside analogues for the treatment of human immunodeficiency virus. Biochem Pharmacol. 1996;51(6):731–6.

    Article  CAS  PubMed  Google Scholar 

  156. Villahermosa ML, Martinez-Irujo JJ, Cabodevilla F, Santiago E. Synergistic inhibition of HIV-1 reverse transcriptase by combinations of chain-terminating nucleotides. Biochemistry. 1997;36(43):13223–31.

    Article  CAS  PubMed  Google Scholar 

  157. Nijhuis M, Schuurman R, de Jong D, van Leeuwen R, Lange J, Danner S, Keulen W, de Groot T, Boucher CA. Lamivudine-resistant human immunodeficiency virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to zidovudine in vivo. J Infect Dis. 1997;176(2):398–405.

    Article  CAS  PubMed  Google Scholar 

  158. Das K, Bandwar RP, White KL, Feng JY, Sarafianos SG, Tuske S, Tu X, Clark Jr AD, Boyer PL, Hou X, Gaffney BL, Jones RA, Miller MD, Hughes SH, Arnold E. Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance. J Biol Chem. 2009;284(50):35092–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. White KL, Chen JM, Feng JY, Margot NA, Ly JK, Ray AS, Macarthur HL, McDermott MJ, Swaminathan S, Miller MD. The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations. Antivir Ther. 2006;11(2):155–63.

    CAS  PubMed  Google Scholar 

  160. Gotte M, Arion D, Parniak MA, Wainberg MA. The M184V mutation in the reverse transcriptase of human immunodeficiency virus type 1 impairs rescue of chain-terminated DNA synthesis. J Virol. 2000;74(8):3579–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Boyer PL, Sarafianos SG, Arnold E, Hughes SH. The M184V mutation reduces the selective excision of zidovudine 5′-monophosphate (AZTMP) by the reverse transcriptase of human immunodeficiency virus type 1. J Virol. 2002;76(7):3248–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Naeger LK, Margot NA, Miller MD. Increased drug susceptibility of HIV-1 reverse transcriptase mutants containing M184V and zidovudine-associated mutations: analysis of enzyme processivity, chain-terminator removal and viral replication. Antivir Ther. 2001;6(2):115–26.

    CAS  PubMed  Google Scholar 

  163. Miranda LR, Gotte M, Liang F, Kuritzkes DR. The L74V mutation in human immunodeficiency virus type 1 reverse transcriptase counteracts enhanced excision of zidovudine monophosphate associated with thymidine analog resistance mutations. Antimicrob Agents Chemother. 2005;49(7):2648–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Frankel FA, Marchand B, Turner D, Gotte M, Wainberg MA. Impaired rescue of chain-terminated DNA synthesis associated with the L74V mutation in human immunodeficiency virus type 1 reverse transcriptase. Antimicrob Agents Chemother. 2005;49(7):2657–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Parikh UM, Barnas DC, Faruki H, Mellors JW. Antagonism between the HIV-1 reverse-transcriptase mutation K65R and thymidine-analogue mutations at the genomic level. J Infect Dis. 2006;194(5):651–60.

    Article  CAS  PubMed  Google Scholar 

  166. Huang H, Chopra R, Verdine GL, Harrison SC. Structure of a covalently trapped catalytic complex of HIV-1 reverse transcriptase: implications for drug resistance. Science. 1998;282(5394):1669–75.

    Article  CAS  PubMed  Google Scholar 

  167. Romano L, Venturi G, Bloor S, Harrigan R, Larder BA, Major JC, Zazzi M. Broad nucleoside-analogue resistance implications for human immunodeficiency virus type 1 reverse-transcriptase mutations at codons 44 and 118. J Infect Dis. 2002;185(7):898–904.

    Article  CAS  PubMed  Google Scholar 

  168. Stoeckli TC, MaWhinney S, Uy J, Duan C, Lu J, Shugarts D, Kuritzkes DR. Phenotypic and genotypic analysis of biologically cloned human immunodeficiency virus type 1 isolates from patients treated with zidovudine and lamivudine. Antimicrob Agents Chemother. 2002;46(12):4000–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Sluis-Cremer N, Moore K, Radzio J, Sonza S, Tachedjian G. N348I in HIV-1 reverse transcriptase decreases susceptibility to tenofovir and etravirine in combination with other resistance mutations. AIDS. 2010;24(2):317–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Radzio J, Yap SH, Tachedjian G, Sluis-Cremer N. N348I in reverse transcriptase provides a genetic pathway for HIV-1 to select thymidine analogue mutations and mutations antagonistic to thymidine analogue mutations. AIDS. 2010;24(5):659–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. von Wyl V, Ehteshami M, Symons J, Burgisser P, Nijhuis M, Demeter LM, Yerly S, Boni J, Klimkait T, Schuurman R, Ledergerber B, Gotte M, Gunthard HF. Epidemiological and biological evidence for a compensatory effect of connection domain mutation N348I on M184V in HIV-1 reverse transcriptase. J Infect Dis. 2010;201(7):1054–62.

    Article  CAS  Google Scholar 

  172. Schinazi RF. Combined therapeutic modalities for viral infections—rationale and clinical potential. In: Chou T-C, Rideout DC, editors. Synergism and antagonism in chemotherapy. Orlando, Fl: Academic; 1991. p. 110–81.

    Google Scholar 

  173. Wong A. The HIV pipeline. Nat Rev Drug Discov. 2014;13(9):649–50.

    Article  CAS  PubMed  Google Scholar 

  174. Services., D.o.H.a.H. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2015. http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.

  175. Masho SW, Wang CL, Nixon DE. Review of tenofovir-emtricitabine. Ther Clin Risk Manag. 2007;3(6):1097–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Miller MD, Haddad M, Su C, Gibbs C, McColl DJ, Guyer B. Trends in HIV-1 reverse transcriptase resistance-associated mutations and antiretroviral prescription data from 2003–2010. Antivir Ther. 2012;17(6):993–9.

    Article  CAS  PubMed  Google Scholar 

  177. Munoz de Benito RM, Arribas Lopez JR. Tenofovir disoproxil fumarate-emtricitabine coformulation for once-daily dual NRTI backbone. Expert Rev Anti Infect Ther. 2006;4(4):523–35.

    Article  CAS  PubMed  Google Scholar 

  178. Schinazi RF. Dead viruses don’t mutate. Int Antiviral News. 1997;5(8):122.

    Google Scholar 

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Acknowledgements

This work was supported in part by NIH grant 1RO1MH100999-01 and 5P30-AI-50409 (CFAR).

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Authors and Affiliations

  1. Department of Pediatrics, Laboratory of Biochemical Pharmacology, Center for AIDS Research, Emory University School of Medicine, Atlanta, GA, USA

    Brian D. Herman Ph.D., Robert A. Domaoal Ph.D., Maryam Ehteshami Ph.D. & Raymond F. Schinazi Ph.D., D.Sc.

Authors
  1. Brian D. Herman Ph.D.
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  2. Robert A. Domaoal Ph.D.
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  3. Maryam Ehteshami Ph.D.
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  4. Raymond F. Schinazi Ph.D., D.Sc.
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Correspondence to Raymond F. Schinazi Ph.D., D.Sc. .

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Editors and Affiliations

  1. Treiber Therapeutics, Cambridge, Massachusetts, USA

    Douglas L. Mayers

  2. Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA

    Jack D. Sobel

  3. Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada

    Marc Ouellette

  4. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Keith S. Kaye

  5. Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Dror Marchaim

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Herman, B.D., Domaoal, R.A., Ehteshami, M., Schinazi, R.F. (2017). Resistance Mechanisms to HIV-1 Nucleoside Reverse Transcriptase Inhibitors. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_33

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