Advertisement

HIV Protease Inhibitor Resistance

  • Annemarie M. J. Wensing
  • Axel Fun
  • Monique Nijhuis
Reference work entry

Abstract

HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs) , based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of structure-based drug design. The introduction of first-generation PIs marked the start of combination antiretroviral therapy . However, low bioavailability, high pill burden, and toxicity ultimately reduced adherence and limited long-term viral inhibition. Therapy failure was often associated with multiple protease inhibitor resistance mutations, both in the viral protease and its substrate (HIV gag protein), displaying a broad spectrum of resistance mechanisms. Unfortunately, selection of protease inhibitor resistance mutations often resulted in cross-resistance to other PIs.

Therefore, second-generation approaches were imperative. Coadministration of a cytochrome P-450 3A4 inhibitor greatly improved the plasma concentration of PIs in the patient. A second advance was the development of PIs that were efficacious against first-generation PI-resistant HIV. Both approaches increased the number of protease mutations required by the virus to develop clinically relevant resistance, thereby raising the genetic barrier towards PI resistance. These improvements greatly contributed to the success of PI-based therapy.

Keywords

Antiretroviral therapy protease inhibitors Evolution HIV Mechanisms of resistance Protease Resistance 

Notes

Acknowledgements

We thank Dr. Pavlina Rezacova from the Institute of Organic Chemistry and Biochemistry Institute of Molecular Genetics in Prague, Czech Republic, for preparing Fig. 3. Funding resource: the Netherlands Organization for Scientific Research (NWO) VIDI Grant (91796349).

References

  1. Abecasis AB, Deforche K, Snoeck J et al (2005) Protease mutation M89I/V is linked to therapy failure in patients infected with the HIV-1 non-B subtypes C, F or G. AIDS 19(16):1799–1806PubMedCrossRefGoogle Scholar
  2. Abecasis AB, Deforche K, Bacheler LT et al (2006) Investigation of baseline susceptibility to protease inhibitors in HIV-1 subtypes C, F, G and CRF02_AG. Antivir Ther 11(5):581–589PubMedGoogle Scholar
  3. Agniswamy J, Sayer JM, Weber IT, Louis JM (2012) Terminal interface conformations modulate dimer stability prior to amino terminal autoprocessing of HIV-1 protease. Biochemistry 51(5):1041–1050PubMedPubMedCentralCrossRefGoogle Scholar
  4. Amiel C, Charpentier C, Désiré N et al (2011) Long-term follow-up of 11 protease inhibitor (PI)-naïve and PI-treated HIV-infected patients harbouring virus with insertions in the HIV-1 protease gene. HIV Med 12(3):138–144PubMedCrossRefGoogle Scholar
  5. Arastéh K, Yeni P, Pozniak A et al (2009) Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther 14(6):859–864PubMedCrossRefGoogle Scholar
  6. Arribas JR, Clumeck N, Nelson M, Hill A, van Delft Y, Moecklinghoff C (2012) The MONET trial: week 144 analysis of the efficacy of darunavir/ritonavir (DRV/r) monotherapy versus DRV/r plus two nucleoside reverse transcriptase inhibitors, for patients with viral load <50 HIV-1 RNA copies/mL at baseline. HIV Med 13(7):398–405PubMedCrossRefGoogle Scholar
  7. Arvieux C, Tribut O (2005) Amprenavir or fosamprenavir plus ritonavir in HIV infection: pharmacology, efficacy and tolerability profile. Drugs 65(5):633–659PubMedCrossRefGoogle Scholar
  8. Atkinson B, Isaacson J, Knowles M, Mazabel E, Patick AK (2000) Correlation between human immunodeficiency virus genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine. J Infect Dis 182(2):420–427PubMedCrossRefGoogle Scholar
  9. Balagam R, Singh V, Sagi AR, Dixit NM (2011) Taking multiple infections of cells and recombination into account leads to small within-host effective-population-size estimates of HIV-1. PLoS One 6(1):e14531PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bally F, Martinez R, Peters S, Sudre P, Telenti A (2000) Polymorphism of HIV type 1 gag p7/p1 and p1/p6 cleavage sites: clinical significance and implications for resistance to protease inhibitors. AIDS Res Hum Retroviruses 16(13):1209–1213PubMedCrossRefGoogle Scholar
  11. Bierman WFW, van Agtmael MA, Nijhuis M, Danner SA, Boucher CAB (2009) HIV monotherapy with ritonavir-boosted protease inhibitors: a systematic review. AIDS 23(3):279–291PubMedCrossRefGoogle Scholar
  12. Borman AM, Paulous S, Clavel F (1996) Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug. J Gen Virol 77(Pt 3):419–426PubMedCrossRefGoogle Scholar
  13. Boyd MA, Srasuebkul P, Khongphattanayothin M et al (2006) Boosted versus unboosted indinavir with zidovudine and lamivudine in nucleoside pre-treated patients: a randomized, open-label trial with 112 weeks of follow-up (HIV-NAT 005). Antivir Ther 11(2):223–232PubMedGoogle Scholar
  14. Brown AJ (1997) Analysis of HIV-1 env gene sequences reveals evidence for a low effective number in the viral population. Proc Natl Acad Sci U S A 94(5):1862–1865PubMedPubMedCentralCrossRefGoogle Scholar
  15. Brown AJ, Richman DD (1997) HIV-1: gambling on the evolution of drug resistance? Nat Med 3(3):268–271PubMedCrossRefGoogle Scholar
  16. Brumme ZL, Chan KJ, Dong WW et al (2003) Prevalence and clinical implications of insertions in the HIV-1 p6Gag N-terminal region in drug-naive individuals initiating antiretroviral therapy. Antivir Ther 8(2):91–96PubMedGoogle Scholar
  17. Cahn P, Villacian J, Lazzarin A et al (2006) Ritonavir-boosted tipranavir demonstrates superior efficacy to ritonavir-boosted protease inhibitors in treatment-experienced HIV-infected patients: 24-week results of the RESIST-2 trial. Clin Infect Dis 43(10):1347–1356PubMedCrossRefGoogle Scholar
  18. Cameron DW, Japour AJ, Xu Y et al (1999) Ritonavir and saquinavir combination therapy for the treatment of HIV infection. AIDS 13(2):213–224PubMedCrossRefGoogle Scholar
  19. Cane PA, de Ruiter A, Rice P, Wiselka M, Fox R, Pillay D (2001) Resistance-associated mutations in the human immunodeficiency virus type 1 subtype c protease gene from treated and untreated patients in the United Kingdom. J Clin Microbiol 39(7):2652–2654PubMedPubMedCentralCrossRefGoogle Scholar
  20. Cardiello PG, Monhaphol T, Mahanontharit A et al (2003) Pharmacokinetics of once-daily saquinavir hard-gelatin capsules and saquinavir soft-gelatin capsules boosted with ritonavir in HIV-1-infected subjects. J Acquir Immune Defic Syndr 32(4):375–379PubMedCrossRefGoogle Scholar
  21. Clavel F, Mammano F (2010) Role of Gag in HIV resistance to protease inhibitors. Viruses 2(7):1411–1426PubMedPubMedCentralCrossRefGoogle Scholar
  22. Coffin JM (1995) HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267(5197):483–489PubMedCrossRefGoogle Scholar
  23. Cohen C, Nieto-Cisneros L, Zala C et al (2005) Comparison of atazanavir with lopinavir/ritonavir in patients with prior protease inhibitor failure: a randomized multinational trial. Curr Med Res Opin 21(10):1683–1692PubMedCrossRefGoogle Scholar
  24. Collier AC, Coombs RW, Schoenfeld DA et al (1996) Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med 334(16):1011–1017PubMedCrossRefGoogle Scholar
  25. Colonno R, Rose R, McLaren C, Thiry A, Parkin N, Friborg J (2004) Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. J Infect Dis 189(10):1802–1810PubMedCrossRefGoogle Scholar
  26. Condra JH, Holder DJ, Schleif WA et al (1996) Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J Virol 70(12):8270–8276PubMedPubMedCentralGoogle Scholar
  27. Conradie F, Sanne I, Venter W, Eron J (2004) Failure of lopinavir-ritonavir (Kaletra)-containing regimen in an antiretroviral-naive patient. AIDS 18(7):1084–1085PubMedCrossRefGoogle Scholar
  28. Côté HC, Brumme ZL, Harrigan PR (2001) Human immunodeficiency virus type 1 protease cleavage site mutations associated with protease inhibitor cross-resistance selected by indinavir, ritonavir, and/or saquinavir. J Virol 75(2):589–594PubMedPubMedCentralCrossRefGoogle Scholar
  29. Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS (1991) Antiviral properties of Ro 31–8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Res 16(4):295–305PubMedCrossRefGoogle Scholar
  30. Croteau G, Doyon L, Thibeault D, McKercher G, Pilote L, Lamarre D (1997) Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol 71(2):1089–1096PubMedPubMedCentralGoogle Scholar
  31. Dam E, Quercia R, Glass B et al (2009) Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog 5(3):e1000345PubMedPubMedCentralCrossRefGoogle Scholar
  32. Danner SA, Carr A, Leonard JM et al (1995) A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. N Engl J Med 333(23):1528–1533PubMedCrossRefGoogle Scholar
  33. Davis MR, Jiang J, Zhou J, Freed EO, Aiken C (2006) A mutation in the human immunodeficiency virus type 1 Gag protein destabilizes the interaction of the envelope protein subunits gp120 and gp41. J Virol 80(5):2405–2417PubMedPubMedCentralCrossRefGoogle Scholar
  34. Davis DA, Soule EE, Davidoff KS, Daniels SI, Naiman NE, Yarchoan R (2012) Activity of human immunodeficiency virus type 1 protease inhibitors against the initial autocleavage in Gag-Pol polyprotein processing. Antimicrob Agents Chemother 56(7):3620–3628PubMedPubMedCentralCrossRefGoogle Scholar
  35. De Meyer S, Azijn H, Surleraux D et al (2005) TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 49(6):2314–2321PubMedPubMedCentralCrossRefGoogle Scholar
  36. de Meyer S, Vangeneugden T, van Baelen B et al (2008) Resistance profile of darunavir: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses 24(3):379–388PubMedCrossRefGoogle Scholar
  37. De Meyer S, Lathouwers E, Dierynck I et al (2009) Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients. AIDS 23(14):1829–1840PubMedCrossRefGoogle Scholar
  38. de Oliveira T, Engelbrecht S, Janse van Rensburg E et al (2003) Variability at human immunodeficiency virus type 1 subtype C protease cleavage sites: an indication of viral fitness? J Virol 77(17):9422–9430PubMedPubMedCentralCrossRefGoogle Scholar
  39. Delaugerre C, Flandre P, Chaix ML et al (2009) Protease inhibitor resistance analysis in the MONARK trial comparing first-line lopinavir-ritonavir monotherapy to lopinavir-ritonavir plus zidovudine and lamivudine triple therapy. Antimicrob Agents Chemother 53(7):2934–2939PubMedPubMedCentralCrossRefGoogle Scholar
  40. Domingo E, Escarmís C, Sevilla N et al (1996) Basic concepts in RNA virus evolution. FASEB J 10(8):859–864PubMedGoogle Scholar
  41. Doyon L, Croteau G, Thibeault D, Poulin F, Pilote L, Lamarre D (1996) Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. J Virol 70(6):3763–3769PubMedPubMedCentralGoogle Scholar
  42. Doyon L, Payant C, Brakier-Gingras L, Lamarre D (1998) Novel Gag-Pol frameshift site in human immunodeficiency virus type 1 variants resistant to protease inhibitors. J Virol 72(7):6146–6150PubMedPubMedCentralGoogle Scholar
  43. Doyon L, Tremblay S, Bourgon L, Wardrop E, Cordingley MG (2005) Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. Antiviral Res 68(1):27–35PubMedCrossRefGoogle Scholar
  44. Drusano GL, Bilello JA, Stein DS et al (1998) Factors influencing the emergence of resistance to indinavir: role of virologic, immunologic, and pharmacologic variables. J Infect Dis 178(2):360–367PubMedCrossRefGoogle Scholar
  45. Erickson-Viitanen S, Manfredi J, Viitanen P et al (1989) Cleavage of HIV-1 gag polyprotein synthesized in vitro: sequential cleavage by the viral protease. AIDS Res Hum Retroviruses 5(6):577–591PubMedCrossRefGoogle Scholar
  46. Eron J, Yeni P, Gathe J et al (2006) The KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet 368(9534):476–482PubMedCrossRefGoogle Scholar
  47. Fleury HJ, Toni T, Lan NT et al (2006) Susceptibility to antiretroviral drugs of CRF01_AE, CRF02_AG, and subtype C viruses from untreated patients of Africa and Asia: comparative genotypic and phenotypic data. AIDS Res Hum Retroviruses 22(4):357–366PubMedCrossRefGoogle Scholar
  48. Frater J (2002) The impact of HIV-1 subtype on the clinical response on HAART. J HIV Ther 7(4):92–96PubMedGoogle Scholar
  49. Friend J, Parkin N, Liegler T, Martin JN, Deeks SG (2004) Isolated lopinavir resistance after virological rebound of a ritonavir/lopinavir-based regimen. AIDS 18(14):1965–1966PubMedCrossRefGoogle Scholar
  50. Fun A, Wensing AMJ, Verheyen J, Nijhuis M (2012) Human immunodeficiency virus gag and protease: partners in resistance. Retrovirology 9Google Scholar
  51. Gallego O, de Mendoza C, Corral A, Soriano V (2003) Changes in the human immunodeficiency virus p7-p1-p6 gag gene in drug-naive and pretreated patients. J Clin Microbiol 41(3):1245–1247PubMedPubMedCentralCrossRefGoogle Scholar
  52. Gartland M, Group AS (2001) AVANTI 3: a randomized, double-blind trial to compare the efficacy and safety of lamivudine plus zidovudine versus lamivudine plus zidovudine plus nelfinavir in HIV-1-infected antiretroviral-naive patients. Antivir Ther 6(2):127–134PubMedGoogle Scholar
  53. Gatanaga H, Suzuki Y, Tsang H et al (2002) Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors. J Biol Chem 277(8):5952–5961PubMedCrossRefGoogle Scholar
  54. Gathe J, Cooper DA, Farthing C et al (2006) Efficacy of the protease inhibitors tipranavir plus ritonavir in treatment-experienced patients: 24-week analysis from the RESIST-1 trial. Clin Infect Dis 43(10):1337–1346PubMedCrossRefGoogle Scholar
  55. Ghosn J, Delaugerre C, Flandre P et al (2011) Polymorphism in Gag gene cleavage sites of HIV-1 non-B subtype and virological outcome of a first-line lopinavir/ritonavir single drug regimen. PLoS One 6(9):e24798PubMedPubMedCentralCrossRefGoogle Scholar
  56. Gilliam BL, Chan-Tack KM, Qaqish RB, Rode RA, Fantry LE, Redfield RR (2006) Successful treatment with atazanavir and lopinavir/ritonavir combination therapy in protease inhibitor-susceptible and protease inhibitor-resistant HIV-infected patients. AIDS Patient Care STDS 20(11):745–759PubMedCrossRefGoogle Scholar
  57. Giordano M, Kelleher T, Colonno RJ, Lazzarin A, Squires K (2006) The effects of the Roche AMPLICOR HIV-1 MONITOR UltraSensitive Test versions 1.0 and 1.5 viral load assays and plasma collection tube type on determination of response to antiretroviral therapy and the inappropriateness of cross-study comparisons. J Clin Virol 35(4):420–425PubMedCrossRefGoogle Scholar
  58. Girnary R, King L, Robinson L, Elston R, Brierley I (2007) Structure-function analysis of the ribosomal frameshifting signal of two human immunodeficiency virus type 1 isolates with increased resistance to viral protease inhibitors. J Gen Virol 88(Pt 1):226–235PubMedCrossRefGoogle Scholar
  59. Gonzalez LM, Santos AF, Abecasis AB et al (2008) Impact of HIV-1 protease mutations A71V/T and T74S on M89I/V-mediated protease inhibitor resistance in subtype G isolates. J Antimicrob Chemother 61(6):1201–1204PubMedCrossRefGoogle Scholar
  60. Götte M (2012) The distinct contributions of fitness and genetic barrier to the development of antiviral drug resistance. Curr Opin Virol 2(5):644–650PubMedCrossRefGoogle Scholar
  61. Grantz Sasková K, Kozísek M, Stray K et al (2013) GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions. J Virol 88:3586–3590PubMedCrossRefGoogle Scholar
  62. Grossman Z, Paxinos EE, Averbuch D et al (2004) Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrob Agents Chemother 48(6):2159–2165PubMedPubMedCentralCrossRefGoogle Scholar
  63. Gulick RM, Mellors JW, Havlir D et al (1997) Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 337(11):734–739PubMedCrossRefGoogle Scholar
  64. Gulnik SV, Suvorov LI, Liu B et al (1995) Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. Biochemistry 34(29):9282–9287PubMedCrossRefGoogle Scholar
  65. Hammer SM, Squires KE, Hughes MD et al (1997) A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 337(11):725–733PubMedCrossRefGoogle Scholar
  66. Haubrich R, Thompson M, Schooley R et al (1999) A phase II safety and efficacy study of amprenavir in combination with zidovudine and lamivudine in HIV-infected patients with limited antiretroviral experience. Amprenavir PROAB2002 Study Team. AIDS 13(17):2411–2420PubMedCrossRefGoogle Scholar
  67. Hicks CB, Cahn P, Cooper DA et al (2006) Durable efficacy of tipranavir-ritonavir in combination with an optimised background regimen of antiretroviral drugs for treatment-experienced HIV-1-infected patients at 48 weeks in the Randomized Evaluation of Strategic Intervention in multi-drug resistant patients with tipranavir (RESIST) studies: an analysis of combined data from two randomised open-label trials. Lancet 368(9534):466–475PubMedCrossRefGoogle Scholar
  68. Huang X, Britto MD, Kear JL et al (2014) The role of select subtype polymorphisms on HIV-1 protease conformational sampling and dynamics. J Biol Chem 289:17203–17214PubMedPubMedCentralCrossRefGoogle Scholar
  69. Jacks T, Power MD, Masiarz FR, Luciw PA, Barr PJ, Varmus HE (1988) Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature 331(6153):280–283PubMedCrossRefGoogle Scholar
  70. Jacobsen H, Haenggi M, Ott M et al (1996) Reduced sensitivity to saquinavir: an update on genotyping from phase I/II trials. Antiviral Res 29(1):95–97PubMedCrossRefGoogle Scholar
  71. Johnson M, Grinsztejn B, Rodriguez C et al (2005) Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS 19(7):685–694PubMedCrossRefGoogle Scholar
  72. Johnson MA, Gathe JC, Podzamczer D et al (2006a) A once-daily lopinavir/ritonavir-based regimen provides noninferior antiviral activity compared with a twice-daily regimen. J Acquir Immune Defic Syndr 43(2):153–160PubMedCrossRefGoogle Scholar
  73. Johnson M, Grinsztejn B, Rodriguez C et al (2006b) 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS 20(5):711–718PubMedCrossRefGoogle Scholar
  74. Johnson VA, Calvez V, Gunthard HF et al (2013) Update of the drug resistance mutations in HIV-1: March 2013. Top Antivir Med 21(1):6–14PubMedGoogle Scholar
  75. Jordan PS, Poon A, Eron J et al (2009) A novel codon insert in protease of clade B HIV type 1. AIDS Res Hum Retroviruses 25(5):547–550PubMedPubMedCentralCrossRefGoogle Scholar
  76. Katlama C, Valantin MA, Algarte-Genin M et al (2010) Efficacy of darunavir/ritonavir maintenance monotherapy in patients with HIV-1 viral suppression: a randomized open-label, noninferiority trial, MONOI-ANRS 136. AIDS 24(15):2365–2374PubMedGoogle Scholar
  77. Kawamura M, Shimano R, Inubushi R et al (1997) Cleavage of Gag precursor is required for early replication phase of HIV-1. FEBS Lett 415(2):227–230PubMedCrossRefGoogle Scholar
  78. Kempf DJ, Marsh KC, Denissen JF et al (1995) ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci U S A 92(7):2484–2488PubMedPubMedCentralCrossRefGoogle Scholar
  79. Kempf DJ, Marsh KC, Kumar G et al (1997) Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother 41(3):654–660PubMedPubMedCentralGoogle Scholar
  80. Kempf DJ, King MS, Bernstein B et al (2004) Incidence of resistance in a double-blind study comparing lopinavir/ritonavir plus stavudine and lamivudine to nelfinavir plus stavudine and lamivudine. J Infect Dis 189(1):51–60PubMedCrossRefGoogle Scholar
  81. Kim EY, Winters MA, Kagan RM, Merigan TC (2001) Functional correlates of insertion mutations in the protease gene of human immunodeficiency virus type 1 isolates from patients. J Virol 75(22):11227–11233PubMedPubMedCentralCrossRefGoogle Scholar
  82. King NM, Prabu-Jeyabalan M, Nalivaika EA, Wigerinck P, de Béthune MP, Schiffer CA (2004) Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Virol 78(21):12012–12021PubMedPubMedCentralCrossRefGoogle Scholar
  83. Kinomoto M, Appiah-Opong R, Brandful JA et al (2005) HIV-1 proteases from drug-naive West African patients are differentially less susceptible to protease inhibitors. Clin Infect Dis 41(2):243–251PubMedCrossRefGoogle Scholar
  84. Kitchen VS, Skinner C, Ariyoshi K et al (1995) Safety and activity of saquinavir in HIV infection. Lancet 345(8955):952–955PubMedCrossRefGoogle Scholar
  85. Knops E, Brakier-Gingras L, Schülter E, Pfister H, Kaiser R, Verheyen J (2012) Mutational patterns in the frameshift-regulating site of HIV-1 selected by protease inhibitors. Med Microbiol Immunol 201(2):213–218PubMedCrossRefGoogle Scholar
  86. Koh Y, Nakata H, Maeda K et al (2003) Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother 47(10):3123–3129PubMedPubMedCentralCrossRefGoogle Scholar
  87. Koh Y, Matsumi S, Das D et al (2007) Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem 282(39):28709–28720PubMedCrossRefGoogle Scholar
  88. Kolli M, Lastere S, Schiffer CA (2006) Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate. Virology 347(2):405–409PubMedCrossRefGoogle Scholar
  89. Kolli M, Stawiski E, Chappey C, Schiffer CA (2009) Human immunodeficiency virus type 1 protease-correlated cleavage site mutations enhance inhibitor resistance. J Virol 83(21):11027–11042PubMedPubMedCentralCrossRefGoogle Scholar
  90. Kouyos RD, Althaus CL, Bonhoeffer S (2006) Stochastic or deterministic: what is the effective population size of HIV-1? Trends Microbiol 14(12):507–511PubMedCrossRefGoogle Scholar
  91. Kozal MJ, Lupo S, DeJesus E et al (2012) A nucleoside- and ritonavir-sparing regimen containing atazanavir plus raltegravir in antiretroviral treatment-naïve HIV-infected patients: SPARTAN study results. HIV Clin Trials 13(3):119–130PubMedCrossRefGoogle Scholar
  92. Kozísek M, Sasková KG, Rezácová P et al (2008) Ninety-nine is not enough: molecular characterization of inhibitor-resistant human immunodeficiency virus type 1 protease mutants with insertions in the flap region. J Virol 82(12):5869–5878PubMedPubMedCentralCrossRefGoogle Scholar
  93. Kozísek M, Henke S, Sasková KG et al (2012) Mutations in HIV-1 gag and pol compensate for the loss of viral fitness caused by a highly mutated protease. Antimicrob Agents Chemother 56(8):4320–4330PubMedPubMedCentralCrossRefGoogle Scholar
  94. Kräusslich HG, Ingraham RH, Skoog MT, Wimmer E, Pallai PV, Carter CA (1989) Activity of purified biosynthetic proteinase of human immunodeficiency virus on natural substrates and synthetic peptides. Proc Natl Acad Sci U S A 86(3):807–811PubMedPubMedCentralCrossRefGoogle Scholar
  95. Kurowski M, Sternfeld T, Sawyer A, Hill A, Möcklinghoff C (2003) Pharmacokinetic and tolerability profile of twice-daily saquinavir hard gelatin capsules and saquinavir soft gelatin capsules boosted with ritonavir in healthy volunteers. HIV Med 4(2):94–100PubMedCrossRefGoogle Scholar
  96. Lambert-Niclot S, Flandre P, Valantin MA et al (2012) Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy. J Antimicrob Chemother 67(6):1470–1474PubMedCrossRefGoogle Scholar
  97. Larrouy L, Chazallon C, Landman R et al (2010) Gag mutations can impact virological response to dual-boosted protease inhibitor combinations in antiretroviral-naïve HIV-infected patients. Antimicrob Agents Chemother 54(7):2910–2919PubMedPubMedCentralCrossRefGoogle Scholar
  98. Larrouy L, Lambert-Niclot S, Charpentier C et al (2011a) Positive impact of HIV-1 gag cleavage site mutations on the virological response to darunavir boosted with ritonavir. Antimicrob Agents Chemother 55(4):1754–1757PubMedPubMedCentralCrossRefGoogle Scholar
  99. Larrouy L, Charpentier C, Landman R et al (2011b) Dynamics of gag-pol minority viral populations in naive HIV-1-infected patients failing protease inhibitor regimen. AIDS 25(17):2143–2148PubMedCrossRefGoogle Scholar
  100. Lee SK, Potempa M, Swanstrom R (2012a) The choreography of HIV-1 proteolytic processing and virion assembly. J Biol Chem 287(49):40867–40874PubMedPubMedCentralCrossRefGoogle Scholar
  101. Lee SK, Potempa M, Kolli M, Özen A, Schiffer CA, Swanstrom R (2012b) Context surrounding processing sites is crucial in determining cleavage rate of a subset of processing sites in HIV-1 Gag and Gag-Pro-Pol polyprotein precursors by viral protease. J Biol Chem 287(16):13279–13290PubMedPubMedCentralCrossRefGoogle Scholar
  102. Lillemark MR, Gerstoft J, Obel N et al (2011) Characterization of HIV-1 from patients with virological failure to a boosted protease inhibitor regimen. J Med Virol 83(3):377–383PubMedCrossRefGoogle Scholar
  103. Lisovsky I, Schader SM, Martinez-Cajas JL, Oliveira M, Moisi D, Wainberg MA (2010) HIV-1 protease codon 36 polymorphisms and differential development of resistance to nelfinavir, lopinavir, and atazanavir in different HIV-1 subtypes. Antimicrob Agents Chemother 54(7):2878–2885PubMedPubMedCentralCrossRefGoogle Scholar
  104. Louis JM, Aniana A, Weber IT, Sayer JM (2011) Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors. Proc Natl Acad Sci U S A 108(22):9072–9077PubMedPubMedCentralCrossRefGoogle Scholar
  105. Ludwig C, Leiherer A, Wagner R (2008) Importance of protease cleavage sites within and flanking human immunodeficiency virus type 1 transframe protein p6* for spatiotemporal regulation of protease activation. J Virol 82(9):4573–4584PubMedPubMedCentralCrossRefGoogle Scholar
  106. Madruga JV, Berger D, McMurchie M et al (2007) Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 370(9581):49–58PubMedCrossRefGoogle Scholar
  107. Maguire M, Shortino D, Klein A et al (2002) Emergence of resistance to protease inhibitor amprenavir in human immunodeficiency virus type 1-infected patients: selection of four alternative viral protease genotypes and influence of viral susceptibility to coadministered reverse transcriptase nucleoside inhibitors. Antimicrob Agents Chemother 46(3):731–738PubMedPubMedCentralCrossRefGoogle Scholar
  108. Mahalingam B, Louis JM, Reed CC et al (1999) Structural and kinetic analysis of drug resistant mutants of HIV-1 protease. Eur J Biochem 263(1):238–245PubMedCrossRefGoogle Scholar
  109. Mammano F, Petit C, Clavel F (1998) Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol 72(9):7632–7637PubMedPubMedCentralGoogle Scholar
  110. Mammano F, Trouplin V, Zennou V, Clavel F (2000) Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug. J Virol 74(18):8524–8531PubMedPubMedCentralCrossRefGoogle Scholar
  111. Manosuthi W, Sungkanuparph S, Ruxrungtham K et al (2008) Plasma levels, safety, and 60-week efficacy of a once-daily double-boosted protease inhibitor regimen of atazanavir, saquinavir, and ritonavir. J Acquir Immune Defic Syndr 47(1):127–129PubMedGoogle Scholar
  112. Mansky LM, Temin HM (1995) Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 69(8):5087–5094PubMedPubMedCentralGoogle Scholar
  113. Markowitz M, Saag M, Powderly WG et al (1995) A preliminary study of ritonavir, an inhibitor of HIV-1 protease, to treat HIV-1 infection. N Engl J Med 333(23):1534–1539PubMedCrossRefGoogle Scholar
  114. Martinez-Cajas JL, Pai NP, Klein MB, Wainberg MA (2009) Differences in resistance mutations among HIV-1 non-subtype B infections: a systematic review of evidence (1996–2008). J Int AIDS Soc 12:11PubMedPubMedCentralCrossRefGoogle Scholar
  115. Martinez-Cajas JL, Wainberg MA, Oliveira M et al (2012) The role of polymorphisms at position 89 in the HIV-1 protease gene in the development of drug resistance to HIV-1 protease inhibitors. J Antimicrob Chemother 67(4):988–994PubMedCrossRefGoogle Scholar
  116. Martinez-Picado J, Savara AV, Sutton L, D’Aquila RT (1999) Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J Virol 73(5):3744–3752PubMedPubMedCentralGoogle Scholar
  117. Martins AN, Arruda MB, Pires AF, Tanuri A, Brindeiro RM (2011) Accumulation of P(T/S)AP late domain duplications in HIV type 1 subtypes B, C, and F derived from individuals failing ARV therapy and ARV drug-naive patients. AIDS Res Hum Retroviruses 27(6):687–692PubMedCrossRefGoogle Scholar
  118. Marzolini C, Buclin T, Decosterd LA, Biollaz J, Telenti A (2001) Nelfinavir plasma levels under twice-daily and three-times-daily regimens: high interpatient and low intrapatient variability. Ther Drug Monit 23(4):394–398PubMedCrossRefGoogle Scholar
  119. Mathez D, Bagnarelli P, Gorin I et al (1997) Reductions in viral load and increases in T lymphocyte numbers in treatment-naive patients with advanced HIV-1 infection treated with ritonavir, zidovudine and zalcitabine triple therapy. Antivir Ther 2(3):175–183PubMedGoogle Scholar
  120. McKinnon JE, Delgado R, Pulido F, Shao W, Arribas JR, Mellors JW (2011) Single genome sequencing of HIV-1 gag and protease resistance mutations at virologic failure during the OK04 trial of simplified versus standard maintenance therapy. Antivir Ther 16(5):725–732PubMedPubMedCentralCrossRefGoogle Scholar
  121. Mills AM, Nelson M, Jayaweera D et al (2009) Once-daily darunavir/ritonavir vs. lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS 23(13):1679–1688PubMedCrossRefGoogle Scholar
  122. Mo H, King MS, King K, Molla A, Brun S, Kempf DJ (2005) Selection of resistance in protease inhibitor-experienced, human immunodeficiency virus type 1-infected subjects failing lopinavir- and ritonavir-based therapy: mutation patterns and baseline correlates. J Virol 79(6):3329–3338PubMedPubMedCentralCrossRefGoogle Scholar
  123. Molina JM, Andrade-Villanueva J, Echevarria J et al (2008) Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet 372(9639):646–655PubMedCrossRefGoogle Scholar
  124. Molla A, Korneyeva M, Gao Q et al (1996) Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med 2(7):760–766PubMedCrossRefGoogle Scholar
  125. Murakami T, Ablan S, Freed EO, Tanaka Y (2004) Regulation of human immunodeficiency virus type 1 Env-mediated membrane fusion by viral protease activity. J Virol 78(2):1026–1031PubMedPubMedCentralCrossRefGoogle Scholar
  126. Murphy RL, Sanne I, Cahn P et al (2003) Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects: 48-week results. AIDS 17(18):2603–2614PubMedCrossRefGoogle Scholar
  127. Naeger LK, Struble KA (2007) Food and Drug Administration analysis of tipranavir clinical resistance in HIV-1-infected treatment-experienced patients. AIDS 21(2):179–185PubMedCrossRefGoogle Scholar
  128. Nalam MN, Ali A, Altman MD et al (2010) Evaluating the substrate-envelope hypothesis: structural analysis of novel HIV-1 protease inhibitors designed to be robust against drug resistance. J Virol 84(10):5368–5378PubMedPubMedCentralCrossRefGoogle Scholar
  129. Navia MA, Fitzgerald PM, McKeever BM et al (1989) Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 337(6208):615–620PubMedCrossRefGoogle Scholar
  130. Nijhuis M, Boucher CAB, Schipper P, Leitner T, Schuurman R, Albert J (1998) Stochastic processes strongly influence HIV-1 evolution during suboptimal protease-inhibitor therapy. Proc Natl Acad Sci U S A 95(24):14441–14446PubMedPubMedCentralCrossRefGoogle Scholar
  131. Nijhuis M, Schuurman R, de Jong D et al (1999) Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS 13(17):2349–2359PubMedCrossRefGoogle Scholar
  132. Nijhuis M, van Maarseveen NM, Lastere S et al (2007) A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism. PLoS Med 4(1):152–163CrossRefGoogle Scholar
  133. Nijhuis M, Wensing AMJ, Bierman WFW et al (2009) Failure of treatment with first-line Lopinavir boosted with ritonavir can be explained by novel resistance pathways with protease mutation 76V. J Infect Dis 200(5):698–709PubMedCrossRefGoogle Scholar
  134. Noble S, Faulds D (1996) Saquinavir. A review of its pharmacology and clinical potential in the management of HIV infection. Drugs 52(1):93–112PubMedCrossRefGoogle Scholar
  135. Notermans DW, Jurriaans S, de Wolf F et al (1998) Decrease of HIV-1 RNA levels in lymphoid tissue and peripheral blood during treatment with ritonavir, lamivudine and zidovudine. Ritonavir/3TC/ZDV Study Group. AIDS 12(2):167–173PubMedCrossRefGoogle Scholar
  136. Oldfield V, Plosker GL (2006) Lopinavir/ritonavir: a review of its use in the management of HIV infection. Drugs 66(9):1275–1299PubMedCrossRefGoogle Scholar
  137. Palella FJ, Delaney KM, Moorman AC et al (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338(13):853–860PubMedCrossRefGoogle Scholar
  138. Parry CM, Kolli M, Myers RE, Cane PA, Schiffer C, Pillay D (2011) Three residues in HIV-1 matrix contribute to protease inhibitor susceptibility and replication capacity. Antimicrob Agents Chemother 55(3):1106–1113PubMedCrossRefGoogle Scholar
  139. Partaledis JA, Yamaguchi K, Tisdale M et al (1995) In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-1 aspartyl protease. J Virol 69(9):5228–5235PubMedPubMedCentralGoogle Scholar
  140. Patick AK, Mo H, Markowitz M et al (1996) Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease. Antimicrob Agents Chemother 40(2):292–297PubMedPubMedCentralGoogle Scholar
  141. Paulsen D, Elston R, Snowden W, Tisdale M, Ross L (2003) Differentiation of genotypic resistance profiles for amprenavir and lopinavir, a valuable aid for choice of therapy in protease inhibitor-experienced HIV-1-infected subjects. J Antimicrob Chemother 52(3):319–323PubMedCrossRefGoogle Scholar
  142. Paulus C, Hellebrand S, Tessmer U, Wolf H, Kräusslich HG, Wagner R (1999) Competitive inhibition of human immunodeficiency virus type-1 protease by the Gag-Pol transframe protein. J Biol Chem 274(31):21539–21543PubMedCrossRefGoogle Scholar
  143. Paulus C, Ludwig C, Wagner R (2004) Contribution of the Gag-Pol transframe domain p6* and its coding sequence to morphogenesis and replication of human immunodeficiency virus type 1. Virology 330(1):271–283PubMedCrossRefGoogle Scholar
  144. Pellegrin I, Breilh D, Montestruc F et al (2002) Virologic response to nelfinavir-based regimens: pharmacokinetics and drug resistance mutations (VIRAPHAR study). AIDS 16(10):1331–1340PubMedCrossRefGoogle Scholar
  145. Pellegrin I, Breilh D, Ragnaud JM et al (2006) Virological responses to atazanavir-ritonavir-based regimens: resistance-substitutions score and pharmacokinetic parameters (Reyaphar study). Antivir Ther 11(4):421–429PubMedGoogle Scholar
  146. Peters S, Muñoz M, Yerly S et al (2001) Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 p6 protein. J Virol 75(20):9644–9653PubMedPubMedCentralCrossRefGoogle Scholar
  147. Petersen ML, Wang Y, van der Laan MJ, Rhee SY, Shafer RW, Fessel WJ (2007) Virologic efficacy of boosted double versus boosted single protease inhibitor therapy. AIDS 21(12):1547–1554PubMedPubMedCentralCrossRefGoogle Scholar
  148. Pettit SC, Moody MD, Wehbie RS et al (1994) The p2 domain of human immunodeficiency virus type 1 Gag regulates sequential proteolytic processing and is required to produce fully infectious virions. J Virol 68(12):8017–8027PubMedPubMedCentralGoogle Scholar
  149. Pettit SC, Everitt LE, Choudhury S, Dunn BM, Kaplan AH (2004) Initial cleavage of the human immunodeficiency virus type 1 GagPol precursor by its activated protease occurs by an intramolecular mechanism. J Virol 78(16):8477–8485PubMedPubMedCentralCrossRefGoogle Scholar
  150. Pettit SC, Lindquist JN, Kaplan AH, Swanstrom R (2005) Processing sites in the human immunodeficiency virus type 1 (HIV-1) Gag-Pro-Pol precursor are cleaved by the viral protease at different rates. Retrovirology 2:66PubMedPubMedCentralCrossRefGoogle Scholar
  151. Plosker GL, Noble S (1999) Indinavir: a review of its use in the management of HIV infection. Drugs 58(6):1165–1203PubMedCrossRefGoogle Scholar
  152. Prabu-Jeyabalan M, Nalivaika E, Schiffer CA (2002) Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes. Structure 10(3):369–381PubMedCrossRefGoogle Scholar
  153. Prabu-Jeyabalan M, Nalivaika EA, Romano K, Schiffer CA (2006) Mechanism of substrate recognition by drug-resistant human immunodeficiency virus type 1 protease variants revealed by a novel structural intermediate. J Virol 80(7):3607–3616PubMedPubMedCentralCrossRefGoogle Scholar
  154. Prado JG, Wrin T, Beauchaine J et al (2002) Amprenavir-resistant HIV-1 exhibits lopinavir cross-resistance and reduced replication capacity. AIDS 16(7):1009–1017PubMedCrossRefGoogle Scholar
  155. Quercia R, Garnier E, Ferré V et al (2005) Salvage therapy with ritonavir-boosted amprenavir/fosamprenavir: virological and immunological response in two years follow-up. HIV Clin Trials 6(2):73–80PubMedCrossRefGoogle Scholar
  156. Rabi SA, Laird GM, Durand CM et al (2013) Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. J Clin Invest 123(9):3848–3860PubMedPubMedCentralCrossRefGoogle Scholar
  157. Rawizza HE, Chaplin B, Meloni ST et al (2013) Accumulation of protease mutations among patients failing second-line antiretroviral therapy and response to salvage therapy in Nigeria. PLoS One 8(9):e73582PubMedPubMedCentralCrossRefGoogle Scholar
  158. Ribera E, Azuaje C, Lopez RM et al (2006) Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen. AIDS 20(8):1131–1139PubMedCrossRefGoogle Scholar
  159. Riddler SA, Haubrich R, DiRienzo AG et al (2008) Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med 358(20):2095–2106PubMedCrossRefGoogle Scholar
  160. Robinson BS, Riccardi KA, Gong YF et al (2000) BMS-232632, a highly potent human immunodeficiency virus protease inhibitor that can be used in combination with other available antiretroviral agents. Antimicrob Agents Chemother 44(8):2093–2099PubMedPubMedCentralCrossRefGoogle Scholar
  161. Rodriguez-French A, Boghossian J, Gray GE et al (2004) The NEAT study: a 48-week open-label study to compare the antiviral efficacy and safety of GW433908 versus nelfinavir in antiretroviral therapy-naive HIV-1-infected patients. J Acquir Immune Defic Syndr 35(1):22–32PubMedCrossRefGoogle Scholar
  162. Sadler BM, Piliero PJ, Preston SL, Lloyd PP, Lou Y, Stein DS (2001) Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers. AIDS 15(8):1009–1018PubMedCrossRefGoogle Scholar
  163. Schapiro JM, Scherer J, Boucher CA et al (2010) Improving the prediction of virological response to tipranavir: the development and validation of a tipranavir-weighted mutation score. Antivir Ther 15(7):1011–1019PubMedCrossRefGoogle Scholar
  164. Schmit JC, Ruiz L, Clotet B et al (1996) Resistance-related mutations in the HIV-1 protease gene of patients treated for 1 year with the protease inhibitor ritonavir (ABT-538). AIDS 10(9):995–999PubMedCrossRefGoogle Scholar
  165. Schrader S, Chuck SK, Rahn LW, Parekh P, Emrich KG (2008) Significant improvements in self-reported gastrointestinal tolerability, quality of life, patient satisfaction, and adherence with lopinavir/ritonavir tablet formulation compared with soft gel capsules. AIDS Res Ther 5:21PubMedPubMedCentralCrossRefGoogle Scholar
  166. Sham HL, Kempf DJ, Molla A et al (1998) ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 42(12):3218–3224PubMedPubMedCentralGoogle Scholar
  167. Shibata J, Sugiura W, Ode H et al (2011) Within-host co-evolution of Gag P453L and protease D30N/N88D demonstrates virological advantage in a highly protease inhibitor-exposed HIV-1 case. Antiviral Res 90(1):33–41PubMedCrossRefGoogle Scholar
  168. Smith GH, Boulassel MR, Klien M et al (2005) Virologic and immunologic response to a boosted double-protease inhibitor-based therapy in highly pretreated HIV-1-infected patients. HIV Clin Trials 6(2):63–72PubMedCrossRefGoogle Scholar
  169. Soulié C, Assoumou L, Ghosn J et al (2009) Nucleoside reverse transcriptase inhibitor-sparing regimen (nonnucleoside reverse transcriptase inhibitor + protease inhibitor) was more likely associated with resistance comparing to nonnucleoside reverse transcriptase inhibitor or protease inhibitor + nucleoside reverse transcriptase inhibitor in the randomized ANRS 121 trial. AIDS 23(12):1605–1608PubMedCrossRefGoogle Scholar
  170. Squires K, Lazzarin A, Gatell JM et al (2004) Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 36(5):1011–1019PubMedCrossRefGoogle Scholar
  171. Stebbing J, Scourfield A, Koh G et al (2009) A multicentre cohort experience with double-boosted protease inhibitors. J Antimicrob Chemother 64(2):434–435PubMedCrossRefGoogle Scholar
  172. Stein DS, Fish DG, Bilello JA, Preston SL, Martineau GL, Drusano GL (1996) A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir). AIDS 10(5):485–492PubMedCrossRefGoogle Scholar
  173. Stray KM, Callebaut C, Glass B et al (2013) Mutations in multiple domains of Gag drive the emergence of in vitro resistance to the phosphonate-containing HIV-1 protease inhibitor GS-8374. J Virol 87(1):454–463PubMedPubMedCentralCrossRefGoogle Scholar
  174. Taiwo B, Zheng L, Gallien S et al (2011) Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262). AIDS 25(17):2113–2122PubMedPubMedCentralCrossRefGoogle Scholar
  175. Tang C, Louis JM, Aniana A, Suh JY, Clore GM (2008) Visualizing transient events in amino-terminal autoprocessing of HIV-1 protease. Nature 455(7213):693–696PubMedPubMedCentralCrossRefGoogle Scholar
  176. Tessmer U, Kräusslich HG (1998) Cleavage of human immunodeficiency virus type 1 proteinase from the N-terminally adjacent p6* protein is essential for efficient Gag polyprotein processing and viral infectivity. J Virol 72(4):3459–3463PubMedPubMedCentralGoogle Scholar
  177. Turner SR, Strohbach JW, Tommasi RA et al (1998) Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J Med Chem 41(18):3467–3476PubMedCrossRefGoogle Scholar
  178. Ulbricht KU, Behrens GM, Stoll M et al (2011) A multicenter, open labeled, randomized, phase III study comparing lopinavir/ritonavir plus atazanavir to lopinavir/ritonavir plus zidovudine and lamivudine in naive HIV-1-infected patients: 48-week analysis of the LORAN trial. Open AIDS J 5:44–50PubMedPubMedCentralCrossRefGoogle Scholar
  179. Vacca JP, Dorsey BD, Schleif WA et al (1994) L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc Natl Acad Sci U S A 91(9):4096–4100PubMedPubMedCentralCrossRefGoogle Scholar
  180. van de Vijver DA, Wensing AM, Angarano G et al (2006) The calculated genetic barrier for antiretroviral drug resistance substitutions is largely similar for different HIV-1 subtypes. J Acquir Immune Defic Syndr 41(3):352–360PubMedCrossRefGoogle Scholar
  181. van Heeswijk RP, Veldkamp A, Mulder JW et al (2001) Combination of protease inhibitors for the treatment of HIV-1-infected patients: a review of pharmacokinetics and clinical experience. Antivir Ther 6(4):201–229PubMedGoogle Scholar
  182. van Maarseveen NM, Andersson D, Lepsik M et al (2012) Modulation of HIV-1 Gag NC/p1 cleavage efficiency affects protease inhibitor resistance and viral replicative capacity. Retrovirology 9Google Scholar
  183. Verheyen J, Knops E, Kupfer B et al (2009) Prevalence of C-terminal gag cleavage site mutations in HIV from therapy-naïve patients. J Infect 58(1):61–67PubMedCrossRefGoogle Scholar
  184. Verheyen J, Verhofstede C, Knops E et al (2010) High prevalence of bevirimat resistance mutations in protease inhibitor-resistant HIV isolates. AIDS 24(5):669–673PubMedCrossRefGoogle Scholar
  185. Voigt E, Wickesberg A, Wasmuth JC et al (2002) First-line ritonavir/indinavir 100/800 mg twice daily plus nucleoside reverse transcriptase inhibitors in a German multicentre study: 48-week results. HIV Med 3(4):277–282PubMedCrossRefGoogle Scholar
  186. von Hentig N, Babacan E, Staszewski S, Stürmer M, Doerr HW, Lötsch J (2007) Predictive factors for response to a boosted dual HIV-protease inhibitor therapy with saquinavir and lopinavir in extensively pre-treated patients. Antivir Ther 12(8):1237–1246Google Scholar
  187. Walmsley S, Bernstein B, King M et al (2002) Lopinavir-ritonavir versus nelfinavir for the initial treatment of HIV infection. N Engl J Med 346(26):2039–2046PubMedCrossRefGoogle Scholar
  188. Walmsley S, Avihingsanon A, Slim J et al (2009) Gemini: a noninferiority study of saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir Immune Defic Syndr 50(4):367–374PubMedCrossRefGoogle Scholar
  189. Whitehurst N, Chappey C, Petropoulos C, Parkin N, Gamarnik A (2003) Polymorphisms in p1-p6/p6* of HIV type 1 can delay protease autoprocessing and increase drug susceptibility. AIDS Res Hum Retroviruses 19(9):779–784PubMedCrossRefGoogle Scholar
  190. Wiegers K, Rutter G, Kottler H, Tessmer U, Hohenberg H, Kräusslich HG (1998) Sequential steps in human immunodeficiency virus particle maturation revealed by alterations of individual Gag polyprotein cleavage sites. J Virol 72(4):2846–2854PubMedPubMedCentralGoogle Scholar
  191. Winters MA, Merigan TC (2005) Insertions in the human immunodeficiency virus type 1 protease and reverse transcriptase genes: clinical impact and molecular mechanisms. Antimicrob Agents Chemother 49(7):2575–2582PubMedPubMedCentralCrossRefGoogle Scholar
  192. Winters MA, Kagan RM, Heseltine PN, Merigan TC (2005) New two-amino acid insertion near codon 70 of the HIV type 1 protease gene. AIDS Res Hum Retroviruses 21(4):311–313PubMedCrossRefGoogle Scholar
  193. Wlodawer A, Miller M, Jaskólski M et al (1989) Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 245(4918):616–621PubMedCrossRefGoogle Scholar
  194. Wyma DJ, Jiang J, Shi J et al (2004) Coupling of human immunodeficiency virus type 1 fusion to virion maturation: a novel role of the gp41 cytoplasmic tail. J Virol 78(7):3429–3435PubMedPubMedCentralCrossRefGoogle Scholar
  195. Zhang YM, Imamichi H, Imamichi T et al (1997) Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol 71(9):6662–6670PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Annemarie M. J. Wensing
    • 1
  • Axel Fun
    • 2
  • Monique Nijhuis
    • 1
  1. 1.Department of Medical MicrobiologyUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.University of CambridgeCambridgeUK

Personalised recommendations