Clinical significance of HIV reverse-transcriptase inhibitor-resistance mutations

Future Microbiology

Volumn 6, Issue 3, 2011, Pages 295-315

  Ibe, Shiro ^a   Sugiura, Wataru ^a,b  

^a NATIONAL HOSPITAL ORGANIZATION NAGOYA MEDICAL CENTER   (Japan)

^b NAGOYA UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

Author keywords

antiretroviral; drug resistance; HIV 1; HIV 2; inhibitor; mutation; reverse transcriptase; review; subtype

Indexed keywords

ABACAVIR; AMPRENAVIR; ATAZANAVIR; DARUNAVIR; DELAVIRDINE; DIDANOSINE; EFAVIRENZ; EMTRICITABINE; ENFUVIRTIDE; ETRAVIRINE; FOSAMPRENAVIR; INDINAVIR; LAMIVUDINE; LOPINAVIR; LOPINAVIR PLUS RITONAVIR; MARAVIROC; NELFINAVIR; NEVIRAPINE; RALTEGRAVIR; RIBONUCLEASE; RITONAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; SAQUINAVIR; STAVUDINE; TENOFOVIR; TENOFOVIR DISOPROXIL; THYMIDINE DERIVATIVE; TIPRANAVIR; UNINDEXED DRUG; VALINE; ZALCITABINE; ZIDOVUDINE;

DRUG RESISTANCE; GENOTYPE; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS 1 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS 2 INFECTION; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IN VITRO STUDY; MUTATION; NONHUMAN; PRIORITY JOURNAL; REVIEW;

AMINO ACID SUBSTITUTION; ANTI-HIV AGENTS; DRUG RESISTANCE, VIRAL; HIV INFECTIONS; HIV REVERSE TRANSCRIPTASE; HIV-1; HIV-2; HUMANS; MUTATION, MISSENSE;

HUMAN IMMUNODEFICIENCY VIRUS 1; HUMAN IMMUNODEFICIENCY VIRUS 2;

EID: 79953329829     PISSN: 17460913     EISSN: None     Source Type: Journal    
DOI: 10.2217/fmb.11.7     Document Type: Review

References (201)

1. Gallo RC, Sarin PS, Gelmann EP et al.: Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 220, 865-867 (1983).
2. Barré-Sinoussi F, Chermann JC, Rey F et al.: Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 220, 868-871 (1983).
3. Kanki PJ, Barin F, M'Boup S et al.: New human T-lymphotropic retrovirus related to simian T-lymphotropic virus type III (STLV-IIIAGM). Science 232, 238-243 (1986).
4. Clavel F, Guétard D, Brun-Vézinet F et al.: Isolation of a new human retrovirus from West African patients with AIDS. Science 233, 343-346 (1986).
5. Collier AC, Coombs RW, Schoenfeld DA et al.: Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N. Engl. J. Med. 334, 1011-1017 (1996).
6. D'Aquila RT, Hughes MD, Johnson VA et al.: Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann. Intern. Med. 124, 1019-1030 (1996).
7. Chun TW, Stuyver L, Mizell SB et al.: Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc. Natl Acad. Sci. USA 94, 13193-13197 (1997).
8. Wong JK, Hezareh M, Günthard HF et al.: Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science 278, 1291-1295 (1997).
9. Finzi D, Hermankova M, Pierson T et al.: Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science 278, 1295-1300 (1997).
10. + count-guided interruption of antiretroviral treatment. N. Engl. J. Med. 355, 2283-2296 (2006).
11. Preston BD, Poiesz BJ, Loeb LA: Fidelity of HIV-1 reverse transcriptase. Science 242, 1168-1171 (1988).
12. Roberts JD, Bebenek K, Kunkel TA: The accuracy of reverse transcriptase from HIV-1. Science 242, 1171-1173 (1988).
13. 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. 69, 5087-5094 (1995).
14. Mansky LM: Forward mutation rate of human immunodeficiency virus type 1 in a T lymphoid cell line. AIDS Res. Hum. Retroviruses 12, 307-314 (1996).
15. Gao F, Chen Y, Levy DN, Conway JA, Kepler TB, Hui H: Unselected mutations in the human immunodeficiency virus type 1 genome are mostly nonsynonymous and often deleterious. J. Virol. 78, 2426-2433 (2004).
16. Huang KJ, Wooley DP: A new cell-based assay for measuring the forward mutation rate of HIV-1. J. Virol. Methods 124, 95-104 (2005).
17. Abram ME, Ferris AL, Shao W, Alvord WG, Hughes SH: Nature, position, and frequency of mutations made in a single cycle of HIV-1 replication. J. Virol. 84, 9864-9878 (2010).
18. Coffin JM: HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267, 483-489 (1995).
19. Perelson AS, Neumann AU, Markowitz M, Leonard JM, Ho DD: HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science 271, 1582-1586 (1996).
20. Kohlstaedt LA, Wang J, Friedman JM, Rice PA, Steitz TA: Crystal structure at 3.5 Å resolution of HIV-1 reverse transcriptase complexed with an inhibitor. Science 256, 1783-1790 (1992).
21. Jacobo-Molina A, Ding J, Nanni RG et al.: 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, 6320-6324 (1993).
22. 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 282, 1669-1675 (1998).
23. Mitsuya H, Weinhold KJ, Furman PA et al.: 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. USA 82, 7096-7100 (1985).
24. Mitsuya H, Broder S: Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy- associated virus (HTLV-III/LAV) by 2′,3′-dideoxynucleosides. Proc. Natl Acad. Sci. USA 83, 1911-1915 (1986).
25. Baba M, Pauwels R, Herdewijn P, De Clercq E, Desmyter J, Vandeputte M: Both 2′,3′-dideoxythymidine and its 2′,3′-unsaturated derivative (2′,3′-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem. Biophys. Res. Commun. 142, 128-134 (1987).
26. Soudeyns H, Yao XI, Gao Q et al.: Antihuman immunodeficiency virus type 1 activity and in vitro toxicity of 2′-deoxy-3′- thiacytidine (BCH-189), a novel heterocyclic nucleoside analog. Antimicrob. Agents Chemother. 35, 1386-1390 (1991).
27. Daluge SM, Good SS, Faletto MB et al.: 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity. Antimicrob. Agents Chemother. 41, 1082-1093 (1997).
28. Balzarini J, Holy A, Jindrich J et al.: Differential antiherpesvirus and antiretrovirus effects of the (S) and (R) enantiomers of acyclic nucleoside phosphonates: potent and selective in vitro and in vivo antiretrovirus activities of (R)-9-(2-phosphonomethoxypropyl)-2,6- diaminopurine. Antimicrob. Agents Chemother. 37, 332-338 (1993).
29. Schinazi RF, McMillan A, Cannon D 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. 36, 2423-2431 (1992).
30. Furman PA, Fyfe JA, St Clair MH 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. USA 83, 8333-8337 (1986).
31. Cheng YC, Dutschman GE, Bastow KF, Sarngadharan MG, Ting RY: Human immunodeficiency virus reverse transcriptase. General properties and its interactions with nucleoside triphosphate analogs. J. Biol. Chem. 262, 2187-2189 (1987).
32. St Clair MH, Richards CA, Spector T et al.: 3′-azido-3′- deoxythymidine triphosphate as an inhibitor and substrate of purified human immunodeficiency virus reverse transcriptase. Antimicrob. Agents Chemother. 31, 1972-1977 (1987).
33. Larder BA, Darby G, Richman DD: HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 243, 1731-1734 (1989).
34. Rooke R, Tremblay M, Soudeyns H et al.: Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group. AIDS 3, 411-415 (1989).
35. Larder BA, Kemp SD: Multiple mutations in HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT). Science 246, 1155-1158 (1989).
36. Johnson VA, Brun-Vézinet F, Clotet B et al.: Update of the drug resistance mutations in HIV-1: December 2009. Top. HIV Med. 17, 138-145 (2009).
37. Shahriar R, Rhee S-Y, Liu TF et al.: Nonpolymorphic human immunodeficiency virus type 1 protease and reverse transcriptase treatment-selected mutations. Antimicrob. Agents Chemother. 53, 4869-4878 (2009). Recent large-scale analysis of nonpolymorphic HIV-1 mutations selected by antiretroviral therapy.
38. Barth RE, van der Loeff MFS, Schuurman R, Hoepelman AIM, Wensing AMJ: Virological follow-up of adult patients in antiretroviral treatment programmes in sub-Saharan Africa: a systematic review. Lancet Infect. Dis. 10, 155-166 (2010). Recent large-scale analysis of virological outcomes and drug-resistance profiles in sub-Saharan Africa. Importantly, almost all the subjects enrolled in the analysis were infected with non-B HIV-1 subtypes (99%).
39. Gupta RK, Hill A, Sawyer AW et al.: Virological monitoring and resistance to first-line highly active antiretroviral therapy in adults infected with HIV-1 treated under WHO guidelines: a systematic review and meta-analysis. Lancet Infect. Dis. 9, 409-417 (2009).
40. McColl DJ, Chappey C, Parkin NT, Miller MD: Prevalence, genotypic associations and phenotypic characterization of K65R, L74V and other HIV-1 RT resistance mutations in a commercial database. Antivir. Ther. 13, 189-197 (2008). Recent large-scale analysis of the nucleos(t)ide analog reverse-transcriptase inhibitor (NRTI)-resistance profile of HIV-1. This paper provides important information on interference between NRTI-resistance mutations.
41. Larder BA, Kemp SD, Harrigan PR: Potential mechanism for sustained antiretroviral efficacy of AZT-3TC combination therapy. Science 269, 696-699 (1995).
42. Kavlick MF, Shirasaka T, Kojima E et al.: Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (-)-2′, 3′-dideoxy-3′-thiacytidine. Antiviral Res. 28, 133-146 (1995).
43. Tisdale M, Kemp SD, Parry NR, Larder BA: Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3′-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc. Natl Acad. Sci. USA 90, 5653-5656 (1993).
44. Boucher CA, Cammack N, Schipper P et al.: High-level resistance to (-) enantiomeric 2′-deoxy-3′-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 37, 2231-2234 (1993).
45. Masquelier B, Descamps D, Carrière I et al.: Zidovudine resensitization and dual HIV-1 resistance to zidovudine and lamivudine in the δ lamivudine roll-over study. Antivir. Ther. 4, 69-77 (1999).
46. Wilson JE, Aulabaugh A, Caligan B et al.: Human immunodeficiency virus type-1 reverse transcriptase. Contribution of Met-184 to binding of nucleoside 5′-triphosphate. J. Biol. Chem. 271, 13656-13662 (1996).
47. Krebs R, Immendörfer U, Thrall SH, Wöhrl BM, Goody RS: Single-step kinetics of HIV-1 reverse transcriptase mutants responsible for virus resistance to nucleoside inhibitors zidovudine and 3-TC. Biochemistry 36, 10292-10300 (1997).
48. 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 38, 9440-9448 (1999).
49. Deval J, White KL, Miller MD et al.: Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations. J. Biol. Chem. 279, 509-516 (2004).
50. Sarafianos SG, Das K, Clark AD Jr et al.: Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with β-branched amino acids. Proc. Natl Acad. Sci. USA 96, 10027-10032 (1999).
51. Hanna GJ, Johnson VA, Kuritzkes DR et al.: Patterns of resistance mutations selected by treatment of human immunodeficiency virus type 1 infection with zidovudine, didanosine, and nevirapine. J. Infect. Dis. 181, 904-911 (2000).
52. Marcelin A-G, Delaugerre C, Wirden M et al.: Thymidine analogue reverse transcriptase inhibitors resistance mutations profiles and association to other nucleoside reverse transcriptase inhibitors resistance mutations observed in the context of virological failure. J. Med. Virol. 72, 162-165 (2004).
53. Miller MD, Margot N, Lu B et al.: Genotypic and phenotypic predictors of the magnitude of response to tenofovir disoproxil fumarate treatment in antiretroviral-experienced patients. J. Infect. Dis. 189, 837-846 (2004).
54. Masquelier B, Tamalet C, Montès B et al.: Genotypic determinants of the virological response to tenofovir disoproxil fumarate in nucleoside reverse transcriptase inhibitorexperienced patients. Antivir. Ther. 9, 315-323 (2004).
55. Cozzi-Lepri A, Ruiz L, Loveday C et al.: Thymidine analogue mutation profiles: factors associated with acquiring specific profiles and their impact on the virological response to therapy. Antivir. Ther. 10, 791-802 (2005).
56. Whitcomb JM, Parkin NT, Chappey C, Hellmann NS, Petropoulos CJ: Broad nucleoside reverse-transcriptase inhibitor cross-resistance in human immunodeficiency virus type 1 clinical isolates. J. Infect. Dis. 188, 992-1000 (2003). Provides outstanding data to understand the impact of TAM accumulation on multi-NRTI resistance in both the presence and absence of the M184V/I mutation.
57. Ross LL, Parkin N, Gerondelis P et al.: Differential impact of thymidine analogue mutations on emtricitabine and lamivudine susceptibility. J. Acquir. Immune Defic. Syndr. 43, 567-570 (2006).
58. Boyer PL, Sarafianos SG, Arnold E, Hughes SH: Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J. Virol. 75, 4832-4842 (2001).
59. 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. USA 95, 13471-13476 (1998).
60. Sarafianos SG, Clark AD Jr, Das K et al.: Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J. 21, 6614-6624 (2002).
61. Tuske S, Sarafianos SG, Clark AD Jr et al.: Structures of HIV-1 RT-DNA complexes before and after incorporation of the anti-AIDS drug tenofovir. Nat. Struct. Mol. Biol. 11, 469-474 (2004).
62. Miller MD, Margot NA, Hertogs K, Larder B, Miller V: Antiviral activity of tenofovir (PMPA) against nucleoside-resistant clinical HIV samples. Nucleosides Nucleotides Nucleic Acids 20, 1025-1028 (2001).
63. Wolf K, Walter H, Beerenwinkel N et al.: Tenofovir resistance and resensitization. Antimicrob. Agents Chemother. 47, 3478-3484 (2003).
64. Lennerstrand J, Hertogs K, Stammers DK, Larder BA: Correlation between viral resistance to zidovudine and resistance at the reverse transcriptase level for a panel of human immunodeficiency virus type 1 mutants. J. Virol. 75, 7202-7205 (2001).
65. 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. 6, 115-126 (2001).
66. 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. 76, 3248-3256 (2002).
67. Gu Z, Gao Q, Fang H et al.: Identification of a mutation at codon 65 in the IKKK motif of reverse transcriptase that encodes human immunodeficiency virus resistance to 2′,3′-dideoxycytidine and 2′,3′- dideoxy-3′- thiacytidine. Antimicrob. Agents Chemother. 38, 275-281 (1994).
68. Zhang D, Caliendo AM, Eron JJ et al.: Resistance to 2′,3′- dideoxycytidine conferred by a mutation in codon 65 of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 38, 282-287 (1994).
69. 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. 41, 1094-1098 (1997).
70. García-Lerma JG, MacInnes H, Bennett D et al.: A novel genetic pathway of human immunodeficiency virus type 1 resistance to stavudine mediated by the K65R mutation. J. Virol. 77, 5685-5693 (2003).
71. Srinivas RV, Fridland A: Antiviral activities of 9-R-2- phosphonomethoxypropyl adenine (PMPA) and bis(isopropyloxymethylcarbonyl) PMPA against various drug-resistant human immunodeficiency virus strains. Antimicrob. Agents Chemother. 42, 1484-1487 (1998).
72. Wainberg MA, Miller MD, Quan Y et al.: In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antivir. Ther. 4, 87-94 (1999).
73. White KL, Margot NA, Ly JK et al.: A combination of decreased NRTI incorporation and decreased excision determines the resistance profile of HIV-1 K65R RT. AIDS 19, 1751-1760 (2005).
74. Gallant JE, Staszewski S, Pozniak AL et al.: Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 292, 191-201 (2004).
75. Gallant JE, DeJesus E, Arribas JR et al.: Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N. Engl. J. Med. 354, 251-260 (2006).
76. Gu Z, Fletcher RS, Arts EJ, Wainberg MA, Parniak MA: The K65R mutant reverse transcriptase of HIV-1 cross-resistant to 2′,3′- dideoxycytidine, 2′,3′-dideoxy-3′- thiacytidine, and 2′,3′-dideoxyinosine shows reduced sensitivity to specific dideoxynucleoside triphosphate inhibitors in vitro. J. Biol. Chem. 269, 28118-28122 (1994).
77. Gu Z, Arts EJ, Parniak MA, Wainberg MA: Mutated K65R recombinant reverse transcriptase of human immunodeficiency virus type 1 shows diminished chain termination in the presence of 2′,3′-dideoxycytidine 5′-triphosphate and other drugs. Proc. Natl Acad. Sci. USA 92, 2760-2764 (1995).
78. Selmi B, Boretto J, Sarfati SR, Guerreiro C, Canard B: Mechanism-based suppression of dideoxynucleotide resistance by K65R human immunodeficiency virus reverse transcriptase using an α-boranophosphate nucleoside analogue. J. Biol. Chem. 276, 48466-48472 (2001).
79. Sluis-Cremer N, Sheen C-W, Zelina S, Torres PSA, 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. 51, 48-53 (2007).
80. White KL, Chen JM, Feng JY et al.: The K65R reverse transcriptase mutation in HIV-1 reverses the excision phenotype of zidovudine resistance mutations. Antivir. Ther. 11, 155-163 (2006).
81. 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 21, 1405-1414 (2007).
82. 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. 80, 4971-4977 (2006).
83. 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. 194, 651-660 (2006).
84. Winston A, Mandalia S, Pillay D, Gazzard B, Pozniak A: The prevalence and determinants of the K65R mutation in HIV-1 reverse transcriptase in tenofovir-naive patients. AIDS 16, 2087-2089 (2002).
85. Valer L, Martín-Carbonero L, de Mendoza C, Corral A, Soriano V: Predictors of selection of K65R: tenofovir use and lack of thymidine analogue mutations. AIDS 18, 2094-2096 (2004).
86. Segondy M, Montes B: Prevalence and conditions of selection of the K65R mutation in the reverse transcriptase gene of HIV-1. J. Acquir. Immune Defic. Syndr. 38, 110-111 (2005).
87. Das K, Bandwar RP, White KL et al.: Structural basis for the role of the K65R mutation in HIV-1 reverse transcriptase polymerization, excision antagonism, and tenofovir resistance. J. Biol. Chem. 284, 35092-35100 (2009).
88. De Antoni A, Foli A, Lisziewicz J, Lori F: Mutations in the pol gene of human immunodeficiency virus type 1 in infected patients receiving didanosine and hydroxyurea combination therapy. J. Infect. Dis. 176, 899-903 (1997).
89. Menéndez-Arias L, Matamoros T, Cases-González CE: Insertions and deletions in HIV-1 reverse transcriptase: consequences for drug resistance and viral fitness. Curr. Pharm. Des. 12, 1811-1825 (2006).
90. Eggink D, Huigen MCDG, Boucher CAB, Götte M, Nijhuis M: Insertions in the β3-β4 loop of reverse transcriptase of human immunodeficiency virus type 1 and their mechanism of action, influence on drug susceptibility and viral replication capacity. Antiviral Res. 75, 93-103 (2007).
91. Winters MA, Coolley KL, Girard YA et al.: A 6-basepair insert in the reverse transcriptase gene of human immunodeficiency virus type 1 confers resistance to multiple nucleoside inhibitors. J. Clin. Invest. 102, 1769-1775 (1998).
92. Sugiura W, Matsuda M, Matsuda Z et al.: Identification of insertion mutations in HIV-1 reverse transcriptase causing multiple drug resistance to nucleoside analogue reverse transcriptase inhibitors. J. Hum. Virol. 2, 146-153 (1999).
93. de Jong JJ, Goudsmit J, Lukashov VV et al.: Insertion of two amino acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs. AIDS 13, 75-80 (1999).
94. Larder BA, Bloor S, Kemp SD et al.: A family of insertion mutations between codons 67 and 70 of human immunodeficiency virus type 1 reverse transcriptase confer multinucleoside analog resistance. Antimicrob. Agents Chemother. 43, 1961-1967 (1999).
95. Rakik A, Ait-Khaled M, Griffin P, Thomas TA, Tisdale M, Kleim JP: A novel genotype encoding a single amino acid insertion and five other substitutions between residues 64 and 74 of the HIV-1 reverse transcriptase confers high-level crossresistance to nucleoside reverse transcriptase inhibitors. Abacavir CNA2007 International Study Group. J. Acquir. Immune Defic. Syndr. 22, 139-145 (1999).
96. Mas A, Parera M, Briones C et al.: Role of a dipeptide insertion between codons 69 and 70 of HIV-1 reverse transcriptase in the mechanism of AZT resistance. EMBO J. 19, 5752-5761 (2000).
97. 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. 76, 9143-9151 (2002).
98. Mas A, Vázquez-Álvarez BM, Domingo E, Menéndez-Arias L: Multidrug-resistant HIV-1 reverse transcriptase: involvement of ribonucleotide-dependent phosphorolysis in cross-resistance to nucleoside analogue inhibitors. J. Mol. Biol. 323, 181-197 (2002).
99. 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. 77, 3871-3877 (2003).
100. White KL, Chen JM, Margot NA et al.: 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. 48, 992-1003 (2004).
101. Shirasaka T, Yarchoan R, O'Brien MC et al.: Changes in drug sensitivity of human immunodeficiency virus type 1 during therapy with azidothymidine, dideoxycytidine, and dideoxyinosine: an in vitro comparative study. Proc. Natl Acad. Sci. USA 90, 562-566 (1993).
102. Shirasaka T, Kavlick MF, Ueno T 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. USA 92, 2398-2402 (1995).
103. Shafer RW, Iversen AK, Winters MA, Aguiniga E, Katzenstein DA, Merigan TC: Drug resistance and heterogeneous long-term virologic responses of human immunodeficiency virus type 1-infected subjects to zidovudine and didanosine combination therapy. The AIDS Clinical Trials Group 143 Virology Team. J. Infect. Dis. 172, 70-78 (1995).
104. Deval J, Selmi B, Boretto J et al.: The molecular mechanism of multidrug resistance by the Q151M human immunodeficiency virus type 1 reverse transcriptase and its suppression using α-boranophosphate nucleotide analogues. J. Biol. Chem. 277, 42097-42104 (2002).
105. Ueno T, Mitsuya H: Comparative enzymatic study of HIV-1 reverse transcriptase resistant to 2′,3′-dideoxynucleotide analogs using the single-nucleotide incorporation assay. Biochemistry 36, 1092-1099 (1997).
106. Merluzzi VJ, Hargrave KD, Labadia M et al.: Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 250, 1411-1413 (1990).
107. Dueweke TJ, Poppe SM, Romero DL et al.: U-90152, a potent inhibitor of human immunodeficiency virus type 1 replication. Antimicrob. Agents Chemother. 37, 1127-1131 (1993).
108. Young SD, Britcher SF, Tran LO et al.: L-743,726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 39, 2602-2605 (1995).
109. Andries K, Azijn H, Thielemans T et al.: TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 48, 4680-4686 (2004).
110. Esnouf RM, Ren J, Hopkins AL et al.: Unique features in the structure of the complex between HIV-1 reverse transcriptase and the bis(heteroaryl) piperazine (BHAP) U-90152 explain resistance mutations for this nonnucleoside inhibitor. Proc. Natl Acad. Sci. USA 94, 3984-3989 (1997).
111. Ren J, Milton J, Weaver KL, Short SA, Stuart DI, Stammers DK: Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Structure 8, 1089-1094 (2000).
112. Das K, Clark AD Jr, Lewi PJ et al.: Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants. J. Med. Chem. 47, 2550-2560 (2004). Important structural study, which explains the potent antiretroviral activity of etravirine and other diarylpyrimidine analogs against both wild-type and non-nucleoside reverse-transcriptase inhibitor (NNRTI)-resistant HIV-1 strains.
113. Spence RA, Kati WM, Anderson KS, Johnson KA: Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science 267, 988-993 (1995).
114. Esnouf R, Ren J, Ross C, Jones Y, Stammers D, Stuart D: Mechanism of inhibition of HIV-1 reverse transcriptase by non-nucleoside inhibitors. Nat. Struct. Biol. 2, 303-308 (1995).
115. Das K, Sarafianos SG, Clark AD Jr, Boyer PL, Hughes SH, Arnold E: Crystal structures of clinically relevant Lys103Asn/Tyr181Cys double mutant HIV-1 reverse transcriptase in complexes with ATP and non-nucleoside inhibitor HBY 097. J. Mol. Biol. 365, 77-89 (2007).
116. Tambuyzer L, Azijn H, Rimsky LT et al.: Compilation and prevalence of mutations associated with resistance to non-nucleoside reverse transcriptase inhibitors. Antivir. Ther. 14, 103-109 (2009). Recent large-scale analysis on the NNRTI-resistance profile of HIV-1.
117. Bacheler L, Jeffrey S, Hanna G et al.: Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J. Virol. 75, 4999-5008 (2001).
118. Wang J, Bambara RA, Demeter LM, Dykes C: Reduced fitness in cell culture of HIV-1 with nonnucleoside reverse transcriptase inhibitor-resistant mutations correlates with relative levels of reverse transcriptase content and RNase H activity in virions. J. Virol. 84, 9377-9389 (2010).
119. Jeffrey JL, Feng JY, Qi CCR, 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. 278, 18971-18979 (2003).
120. Lys,3 that correlate with reductions in replication efficiency. Virology 348, 462-474 (2006).
121. Hsiou Y, Ding J, Das K et al.: The Lys103Asn mutation of HIV-1 RT: a novel mechanism of drug resistance. J. Mol. Biol. 309, 437-445 (2001).
122. Bannister WP, Ruiz L, Cozzi-Lepri A et al.: Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA. AIDS 22, 367-376 (2008).
123. Reuman EC, Rhee S-Y, Holmes SP, Shafer RW: Constrained patterns of covariation and clustering of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations. J. Antimicrob. Chemother. 65, 1477-1485 (2010).
124. Larder BA: 3′c-Azido-3′-deoxythymidine resistance suppressed by a mutation conferring human immunodeficiency virus type 1 resistance to nonnucleoside reverse transcriptase inhibitors. Antimicrob. Agents Chemother. 36, 2664-2669 (1992).
125. Richman DD, Havlir D, Corbeil J et al.: Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy. J. Virol. 68, 1660-1666 (1994).
126. Selmi B, Deval J, Alvarez K et al.: The Y181C substitution in 3′-azido-3′-deoxythymidine-resistant human immunodeficiency virus, type 1, reverse transcriptase suppresses the ATP-mediated repair of the 3′-azido-3′- deoxythymidine 5′-monophosphate-terminated primer. J. Biol. Chem. 278, 40464-40472 (2003).
127. Spence RA, Anderson KS, Johnson KA: HIV-1 reverse transcriptase resistance to nonnucleoside inhibitors. Biochemistry 35, 1054-1063 (1996).
128. Iglesias-Ussel MD, Casado C, Yuste E, Olivares I, López- Galíndez C: In vitro analysis of human immunodeficiency virus type 1 resistance to nevirapine and fitness determination of resistant variants. J. Gen. Virol. 83, 93-101 (2002).
129. Ren J, Nichols C, Bird L et al.: Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors. J. Mol. Biol. 312, 795-805 (2001).
130. Vingerhoets J, Azijn H, Fransen E et al.: TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. J. Virol. 79, 12773-12782 (2005).
131. Marcelin A-G, Flandre P, Descamps D et al.: Factors associated with virological response to etravirine in nonnucleoside reverse transcriptase inhibitor-experienced HIV-1-infected patients. Antimicrob. Agents Chemother. 54, 72-77 (2010).
132. Vingerhoets J, Tambuyzer L, Azijn H et al.: Resistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies. AIDS 24, 503-514 (2010). Recent important study, which identified 17 etravirine-resistance-associated mutations in clinical settings. This study also provides information on a weighted genotypic scoring algorithm for interpreting etravirine resistance.
133. Dau B, Ayers D, Singer J et al.: Connection domain mutations in treatment-experienced patients in the OPTIMA trial. J. Acquir. Immune Defic. Syndr. 54, 160-166 (2010).
134. von Wyl V, Ehteshami M, Demeter LM et al.: HIV-1 reverse transcriptase connection domain mutations: dynamics of emergence and implications for success of combination antiretroviral therapy. Clin. Infect. Dis. 51, 620-628 (2010).
135. Nikolenko GN, Delviks-Frankenberry KA, Palmer S et al.: Mutations in the connection domain of HIV-1 reverse transcriptase increase 3′-azido- 3′-deoxythymidine resistance. Proc. Natl Acad. Sci. USA 104, 317-322 (2007).
136. Yap S-H, Sheen C-W, Fahey J et al.: N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance. PLoS Med. 4, E335 (2007).
137. Hachiya A, Kodama EN, Sarafianos SG et al.: Amino acid mutation N348I in the connection subdomain of human immunodeficiency virus type 1 reverse transcriptase confers multiclass resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J. Virol. 82, 3261-3270 (2008).
138. 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 24, 317-319 (2010).
139. Ehteshami M, Beilhartz GL, Scarth BJ et al.: 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. 283, 22222-22232 (2008).
140. Nikolenko GN, Delviks-Frankenberry KA, Pathak VK: A novel molecular mechanism of dual resistance to nucleoside and nonnucleoside reverse transcriptase inhibitors. J. Virol. 84, 5238-5249 (2010).
141. Biondi MJ, Beilhartz GL, McCormick S, Götte M: N348I in HIV-1 reverse transcriptase can counteract the nevirapine-mediated bias toward RNase H cleavage during plus-strand initiation. J. Biol. Chem. 285, 26966-26975 (2010).
142. Robertson DL, Anderson JP, Bradac JA et al.: HIV-1 nomenclature proposal. In: Human Retroviruses and AIDS 1999. Kuiken CL, Foley B, Hahn B et al. (Eds). Los Alamos National Laboratory, NM, USA, 492-505 (1999).
143. Robertson DL, Anderson JP, Bradac JA et al.: HIV-1 nomenclature proposal. Science 288, 55-56 (2000).
144. Plantier J-C, Leoz M, Dickerson JE et al.: A new human immunodeficiency virus derived from gorillas. Nat. Med. 15, 871-872 (2009).
145. Hemelaar J, Gouws E, Ghys PD, Osmanov S: Global and regional distribution of HIV-1 genetic subtypes and recombinants in 2004. AIDS 20, W13-W23 (2006). Important study, which provides information on the global distribution of HIV-1 subtypes and recombinant forms.
146. Pillay D, Walker AS, Gibb DM et al.: Impact of human immunodeficiency virus type 1 subtypes on virologic response and emergence of drug resistance among children in the Paediatric European Network for Treatment of AIDS (PENTA) 5 trial. J. Infect. Dis. 186, 617-625 (2002).
147. Atlas A, Granath F, Lindström A, Lidman K, Lindbäck S, Alaeus A: Impact of HIV type 1 genetic subtype on the outcome of antiretroviral therapy. AIDS Res. Hum. Retroviruses 21, 221-227 (2005).
148. Soares EAJM, Santos AFA, Sousa TM et al.: Differential drug resistance acquisition in HIV-1 of subtypes B and C. PLoS ONE 2, E730 (2007).
149. Geretti AM, Harrison L, Green H et al.: Effect of HIV-1 subtype on virologic and immunologic response to starting highly active antiretroviral therapy. Clin. Infect. Dis. 48, 1296-1305 (2009). Largest study to analyze the impact of HIV-1 subtypes on virological and immunological responses to HAART.
150. Easterbrook PJ, Smith M, Mullen J et al.: Impact of HIV-1 viral subtype on disease progression and response to antiretroviral therapy. J. Int. AIDS Soc. 13, 4 (2010).
151. Brenner B, Turner D, Oliveira M et al.: A V106M mutation in HIV-1 clade C viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. AIDS 17, F1-F5 (2003).
152. Dumans AT, Soares MA, Machado ES et al.: Synonymous genetic polymorphisms within Brazilian human immunodeficiency virus Type 1 subtypes may influence mutational routes to drug resistance. J. Infect. Dis. 189, 1232-1238 (2004).
153. van de Vijver DA, Wensing AMJ, Angarano G et al.: The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes. J. Acquir. Immune Defic. Syndr. 41, 352-360 (2006). Large-scale and systematic study, which provides important information on the differences in HIV-1 subtype-specific genetic barriers for acquiring drug-resistant amino acid substitutions.
154. Brenner BG, Oliveira M, Doualla-Bell F et al.: HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture. AIDS 20, F9-F13 (2006).
155. Coutsinos D, Invernizzi CF, Xu H et al.: Template usage is responsible for the preferential acquisition of the K65R reverse transcriptase mutation in subtype C variants of human immunodeficiency virus type 1. J. Virol. 83, 2029-2033 (2009).
156. Invernizzi CF, Coutsinos D, Oliveira M, Moisi D, Brenner BG, Wainberg MA: Signature nucleotide polymorphisms at positions 64 and 65 in reverse transcriptase favor the selection of the K65R resistance mutation in HIV-1 subtype C. J. Infect. Dis. 200, 1202-1206 (2009).
157. Varghese V, Wang E, Babrzadeh F et al.: Nucleic acid template and the risk of a PCR-Induced HIV-1 drug resistance mutation. PLoS ONE 5, E10992 (2010).
158. Grossman Z, Istomin V, Averbuch D et al.: Genetic variation at NNRTI resistanceassociated positions in patients infected with HIV-1 subtype C. AIDS 18, 909-915 (2004).
159. Gao F, Yue L, White AT et al.: Human infection by genetically diverse SIVSMrelated HIV-2 in West Africa. Nature 358, 495-499 (1992).
160. Gao F, Yue L, Robertson DL et al.: Genetic diversity of human immunodeficiency virus type 2: evidence for distinct sequence subtypes with differences in virus biology. J. Virol. 68, 7433-7447 (1994).
161. Chen Z, Luckay A, Sodora DL et al.: Human immunodeficiency virus type 2 (HIV-2) seroprevalence and characterization of a distinct HIV-2 genetic subtype from the natural range of simian immunodeficiency virus-infected sooty mangabeys. J. Virol. 71, 3953-3960 (1997).
162. Damond F, Worobey M, Campa P et al.: Identification of a highly divergent HIV type 2 and proposal for a change in HIV type 2 classification. AIDS Res. Hum. Retroviruses 20, 666-672 (2004).
163. Yamaguchi J, Devare SG, Brennan CA: Identification of a new HIV-2 subtype based on phylogenetic analysis of full-length genomic sequence. AIDS Res. Hum. Retroviruses 16, 925-930 (2000).
164. Ibe S, Yokomaku Y, Shiino T et al.: HIV-2 CRF01-AB: first circulating recombinant form of HIV-2. J. Acquir. Immune Defic. Syndr. 54, 241-247 (2010).
165. Whittle H, Morris J, Todd J et al.: HIV-2- infected patients survive longer than HIV-1-infected patients. AIDS 8, 1617-1620 (1994).
166. Marlink R, Kanki P, Thior I et al.: Reduced rate of disease development after HIV-2 infection as compared with HIV-1. Science 265, 1587-1590 (1994).
167. Adjorlolo-Johnson G, De Cock KM, Ekpini E et al.: Prospective comparison of mother-tochild transmission of HIV-1 and HIV-2 in Abidjan, Ivory Coast. JAMA 272, 462-466 (1994).
168. Ota MO, O'Donovan D, Alabi AS et al.: Maternal HIV-1 and HIV-2 infection and child survival in The Gambia. AIDS 14, 435-439 (2000).
169. Schim van der Loeff MF, Jaffar S, Aveika AA et al.: Mortality of HIV-1, HIV-2 and HIV-1/HIV-2 dually infected patients in a clinicbased cohort in The Gambia. AIDS 16, 1775-1783 (2002).
170. + T cell decline in human immunodeficiency virus (HIV) type 1- and HIV-2-infected individuals from Senegal, West Africa. J. Infect. Dis. 185, 905-914 (2002).
171. Witvrouw M, Pannecouque C, Van Laethem K, Desmyter J, De Clercq E, Vandamme AM: Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. AIDS 13, 1477-1483 (1999).
172. Witvrouw M, Pannecouque C, Switzer WM, Folks TM, De Clercq E, Heneine W: Susceptibility of HIV-2, SIV and SHIV to various anti-HIV-1 compounds: implications for treatment and postexposure prophylaxis. Antivir. Ther. 9, 57-65 (2004).
173. Gottlieb GS, Eholié S-P, Nkengasong JN et al.: A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS 22, 2069-2072 (2008).
174. Drylewicz J, Matheron S, Lazaro E et al.: Comparison of viro-immunological marker changes between HIV-1 and HIV-2-infected patients in France. AIDS 22, 457-468 (2008).
175. Toure S, Kouadio B, Seyler C et al.: Rapid scaling-up of antiretroviral therapy in 10,000 adults in Côte d'Ivoire: 2-year outcomes and determinants. AIDS 22, 873-882 (2008).
176. Harries K, Zachariah R, Manzi M et al.: Baseline characteristics, response to and outcome of antiretroviral therapy among patients with HIV-1, HIV-2 and dual infection in Burkina Faso. Trans. R. Soc. Trop. Med. Hyg. 104, 154-161 (2010).
177. + response to antiretroviral therapy according to the HIV type in the IeDEA West Africa collaboration. AIDS 24, 1043-1050 (2010).
178. Guyader M, Emerman M, Sonigo P, Clavel F, Montagnier L, Alizon M: Genome organization and transactivation of the human immunodeficiency virus type 2. Nature 326, 662-669 (1987).
179. Ren J, Bird LE, Chamberlain PP, Stewart-Jones GB, Stuart DI, Stammers DK: Structure of HIV-2 reverse transcriptase at 2.35-Å resolution and the mechanism of resistance to non-nucleoside inhibitors. Proc. Natl Acad. Sci. USA 99, 14410-14415 (2002).
180. Rodés B, Holguín A, Soriano V et al.: Emergence of drug resistance mutations in human immunodeficiency virus type 2-infected subjects undergoing antiretroviral therapy. J. Clin. Microbiol. 38, 1370-1374 (2000).
181. Brandin E, Lindborg L, Gyllensten K et al.: pol gene sequence variation in Swedish HIV-2 patients failing antiretroviral therapy. AIDS Res. Hum. Retroviruses 19, 543-550 (2003).
182. + cell counts, and drug resistance profiles of patients treated in Abidjan, Côte d'Ivoire. AIDS 17(Suppl. 3), S49-S54 (2003).
183. van der Ende ME, Prins JM, Brinkman K et al.: Clinical, immunological and virological response to different antiretroviral regimens in a cohort of HIV-2-infected patients. AIDS 17(Suppl. 3), S55-S61 (2003).
184. Descamps D, Damond F, Matheron S et al.: High frequency of selection of K65R and Q151M mutations in HIV-2 infected patients receiving nucleoside reverse transcriptase inhibitors containing regimen. J. Med. Virol. 74, 197-201 (2004).
185. Colson P, Henry M, Tivoli N et al.: Polymorphism and drug-selected mutations in the reverse transcriptase gene of HIV-2 from patients living in southeastern France. J. Med. Virol. 75, 381-390 (2005).
186. Ruelle J, Roman F, Vandenbroucke A-T et al.: Transmitted drug resistance, selection of resistance mutations and moderate antiretroviral efficacy in HIV-2: analysis of the HIV-2 Belgium and Luxembourg database. BMC Infect. Dis. 8, 21 (2008).
187. Gottlieb GS, Badiane NMD, Hawes SE et al.: Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resouce-limited West Africa. Clin. Infect. Dis. 48, 476-483 (2009).
188. Jallow S, Kaye S, Alabi A et al.: Virological and immunological response to Combivir and emergence of drug resistance mutations in a cohort of HIV-2 patients in The Gambia. AIDS 20, 1455-1458 (2006).
189. Boyer PL, Sarafianos SG, Clark PK, Arnold E, Hughes SH: Why do HIV-1 and HIV-2 use different pathways to develop AZT resistance? PLoS Pathog. 2, E10 (2006). Explains the preference of HIV-2 RT for excision-independent NRTI-resistant pathways compared with HIV-1 RT.
190. Smith RA, Anderson DJ, Pyrak CL, Preston BD, Gottlieb GS: Antiretroviral drug resistance in HIV-2: three amino acid changes are sufficient for classwide nucleoside analogue resistance. J. Infect. Dis. 199, 1323-1326 (2009). Recent study that clearly explains the profile of multi-NRTI resistance in HIV-2.
191. Shafer RW, Schapiro JM: HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. AIDS Rev. 10, 67-84 (2008).
192. Azijn H, Tirry I, Vingerhoets J et al.: TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob. Agents Chemother. 54, 718-727 (2010).
193. Corbau R, Mori J, Phillips C et al.: Lersivirine, a nonnucleoside reverse transcriptase inhibitor with activity against drug-resistant human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 54, 4451-4463 (2010).
194. Tu X, Das K, Han Q et al.: Structural basis of HIV-1 resistance to AZT by excision. Nat. Struct. Mol. Biol. 17, 1202-1209 (2010). Structural study that clearly explains the detailed molecular basis of zidovudine-5′- monophosphate excision by thymidine analog-associated mutations-containing HIV-1 RT. Provides outstanding data, including the crystal structure of TAM-containing HIV-1 RT in a complex with a DNA template-primer and an excision product, AZTppppA.
195. UNAIDS: Introduction. In: 2009 AIDS Epidemic Update. UNAIDS, Geneva, Switzerland, 7-20 (2009) www.unaids.org/en/dataanalysis/epidemiology/
196. World Health Organization (WHO): What to start. In: Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach - 2010 version. WHO, Geneva, Switzerland, 31-40 (2010) www.who.int/hiv/pub/arv/en/
197. The United States Department of Health and Human Services (U.S. DHHS): What to start: initial combination regimens for the antiretroviral-naïve patient. In: Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents - December 1, 2009. US DHHS, USA, 37-59 (2009) http://aidsinfo.nih.gov/Guidelines/
198. European AIDS Clinical Society (EACS): Initial combination regimen for antiretroviral-naïve patient. In: Clinical management and treatment of HIV infected adults in Europe - version 5-2. EACS, Paris, France, 17 (2009) www.europeanaidsclinicalsociety.org/guidelines.asp
199. HIV Sequence Database in the Los Alamos National Laboratory, Los Alamos, USA www.hiv.lanl.gov/
200. HIV-1 genotypic drug resistance interpretation's algorithm (version 19, July 2010), ANRS AC11 Resistance Group, France www.hivfrenchresistance.org/
201. ClinicalTrials.gov: A service of the U.S. National Institutes of Health, USA http://clinicaltrials.gov/