Stanford University HIV Drug Resistance Database - A curated public database designed to represent, store, and analyze the divergent forms of data underlying HIV drug resistance.

PI Resistance Notes

Last updated on Oct 10, 2011
Resistance Matrix Resistance Mutation Comments Resistance Mutation Scores Drug Summaries

Major Protease Inhibitor (PI) Resistance Mutations
 
  30 32 46 47 48 50 54 76 82 84 88 90
Cons D V M I G I I L V I N L
ATV/r   I IL V VM L VTALM   ATFS V S M
DRV/r   I   VA   V LM V F V   
FPV/r   I IL VA   V VTALM V ATSF V   M
IDV/r   I IL V     VTALM V AFTS V S M
LPV/r   I IL VA VM V VTALM V AFTS V   M
NFV N   IL V VM   VTALM   AFTS V DS M
SQV/r         VM   VTALM   AT V S M
TPV/r   I IL VA     VAM   TL V    
MAJOR MUTATIONS: Mutations that are associated with high levels of phenotypic resistance or clinical evidence for reduced virological response. Those in bold red are associated with the highest levels of phenotypic resistance or with the strongest clinical evidence for reduced virological response. Underlined mutations are potential contraindications to the use of the indicated PIs when other alternatives are available. Positions 30, 32, 46, 47, 48, 50, 54, 82, and 84 are in or near (positions 46, 47, and 54) the substrate cleft. (Jacobsen 95; Partaledis 95; Condra 96; Carrillo 98; Patick 98; Schapiro 99; Atkinson 00; Gong 00; Scott 00; Maguire 02a; Parkin 03; Colonno 04; Doyon 05; Kagan 05; Vermeiren 07; De Meyer 08a; Marcelin 08; Sista 08; Van Marck 09; Llibre 10; Rhee 10; Schapiro 10). Positions 76, 88, and 90 interfere with PI susceptibility indirectly (Patick 98; Atkinson 00; Mahalingam 01; Malan 08; Rhee 10; Louis 11).

COMMON RELATIVELY NONPOLYMORPHIC ACCESSORY MUTATIONS: The most well known include L10IVF, V11I, K20TVI, L23I, L24IF, L33F, K43T, F53L, Q58E, A71VTIL, G73STCA, T74PS, N83D, and L89V (Sevin 00; Kempf 01; Maguire 02a; Parkin 03; Wu 03; Ceccherini-Silberstein 04; Johnston 04; Kagan 06; Kozal 06; De Meyer 08b; Descamps 09; Schapiro 10). These mutations reduce PI susceptibility when they occur in combination with other mutations: L10F contributes reduced susceptibility to PIs except TPV; L10IV are primarily accessory. V11I and L89V emerge during DRV/r therapy and contribute decreased susceptibility to DRV/r, FPR/r, and possibly other PIs K20ITV contributes reduced susceptibility to NFV and possibly other PIs. K20I is the consensus residue for subtype G. L23I contributes to NFV resistance. L24I is selected by IDV/r and LPV/r and contributes reduced susceptibility to each of the PIs except TPV/r and DRV/r. L33F is associated with reduced susceptibility to all PIs except IDV/r and SQV/r. K43T is associated with reduced susceptibility to all PIs. F53L are important accessory mutations for ATV/r and SQV/r but may affect other PIs. Q58E, T74P, and N83D are selected by multiple PIs but have only been shown to be associated with a decreased virological response to TPV/r. G73STCA are important accessory mutations for ATV/r and SQV/r particularly in combination with L90M. However, like A71VTIL, these mutations appear to be selected by or contribute decreased susceptibility to each of the PIs. L10IV and A71VT occur in up to 5% of PI-naive viruses, L33F and V11I occur in ~1% of PI-naive viruses, K20I and T74S occur commonly in other subtypes.

RARE VARIANTS AT KNOWN DRUG-RESISTANCE POSITIONS: L10RY, V11L, M46V, G48ASTLQ, F53Y, I54S, V82MC, I84AC, N88TG, and V89T (Camacho 05; Baxter 06; Mo 07; Vermeiren 07; Shahriar 09; Rhee 10);

NON-POLYMORPHIC PI-SELECTED MUTATIONS AT POSITIONS NOT GENERALLY RECOGNIZED AS PI-RESISTANCE POSITIONS: Nonpolymorphic mutations that occur significantly more frequently in PI-experienced compared with PI-naive patients: A22V, E34Q, E35G, K55RN, I66FVL, C67FL, V75I, P79ASD, I85V, T91S, Q92K, and C95F (Carrillo 98; Parkin 03; Wu 03; Ceccherini-Silberstein 04; Svicher 05; Kagan 06; Margerison 08; Shahriar 09).

COMMON HIGHLY POLYMORPHIC COMPENSATORY MUTATIONS: K20R, M36I, I62V, L63P, V77I, and I93L. These mutations compensate for the decreased fitness associated with major PI-resistance mutations (Condra 95; Molla 96; Schock 96; Mammano 98; Martinez-Picado 99; Nijhuis 99; Martinez-Picado 00; Hoffman 03; Clemente 04; Nijhuis 07; Quinones-Mateu 08; Chang 11).

HYPERSUSCEPTIBILITY: I50L increases susceptibility to all PIs except ATV (Weinheimer 05; Sista 08); I50V and I54L increase TPV/r susceptibility (Baxter 06; Schapiro 10); L76V increases ATV, SQV, and TPV susceptibility (Vermeiren 07; Schapiro 10; Wiesmann 11). N88S increases FPV susceptibility (Ziermann 00).

GAG CLEAVAGE AND NON-CLEAVAGE SITE MUTATIONS: Gag cleavage site mutations, particularly those in the 3 region may compensate for the decreased fitness associated with major PI-resistance mutations (Zhang 97; Cote 01; Dauber 02; Maguire 02b; Prabu-Jeyabalan 04; Kolli 06; Verheyen 06; Lambert-Niclot 08b; Knops 10). Other 3 Gag mutations increase Gag-Pol processing, thereby indirectly compensating for decreased fitness associated with PI resistance mutations (Gatanaga 02; Myint 04; Tamiya 04; Nijhuis 07).

GENOTYPIC SUSCEPTIBILITY SCORES: A GSS for DRV/r derived from the POWER trials identified 11 mutations at 10 positions: V11I, V32I, L33F, I47V, I50V, I54LM, G73S, L76V, I84V, L89V (De Meyer 08a; De Meyer 08b; De Meyer 09). T74P was then substituted for G73S in an updated analysis. The DRV/r GSS mutations have generally been reported by others to be the most commonly occurring mutations in patients receiving DRV/r and to be associated with decreased DRV susceptibility (Delaugerre 08; Lambert-Niclot 08a; Van Marck 09; Rhee 10). The weighted GSS for TPV/r derived from clinical trials includes the following mutations: I47V (+4), T74P (+4), V82LT(+4), N83D (+4) Q58E (+3), I84V (+3), M36I (+2), K43T (+2), I54AMV (+2), L10V (1), L33F (1), M46L (+1), L24I (-2), L76V (-2), I50L/V (-4), I54L (-6). Viruses with a total score <=3) are considered susceptible, 3 to 10 intermediate, and >10 resistant (>10) (Baxter 06; Schapiro 10).

INTER-SUBTYPE DIFFERENCES: In several non-B subtypes including C, 01_AE, and G, D30N is less likely to cause NFV resistance than other mutations such as L90M or N88S (Cane 01; Ariyoshi 03; Gonzalez 04; Grossman 04). T74S, which occurs in nearly 10% of subtype C viruses, is also associated with reduced NFV susceptibility (Deforche 06; Vermeiren 07). In subtype B viruses, V82M is a rare 2 base-pair mutation that occurs only in combination with many other PI-resistance mutations (Baxter 06); however, in subtype G viruses (for which the wild type residue at position 82 is I), V82M is caused by a 1-bp mutation that occurs commonly and decreases susceptibility to IDV and possibly other PIs (Camacho 05).

REFERENCES

  • Ariyoshi, K., M. Matsuda, H. Miura, S. Tateishi, K. Yamada and W. Sugiura. Patterns of point mutations associated with antiretroviral drug treatment failure in CRF01_AE (subtype E) infection differ from subtype B infection. J Acquir Immune Defic Syndr. 2003:33;336-342.PubMed
  • Atkinson, B., J. Isaacson, M. Knowles, E. Mazabel and A. K. Patick. Correlation between human immunodeficiency virus genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine. J Infect Dis. 2000:182;420-427.PubMed
  • Baxter, J. D., J. M. Schapiro, C. A. Boucher, V. M. Kohlbrenner, D. B. Hall, J. R. Scherer and D. L. Mayers. Genotypic changes in human immunodeficiency virus type 1 protease associated with reduced susceptibility and virologic response to the protease inhibitor tipranavir. J Virol. 2006:80;10794-10801.PubMed
  • Camacho, R., A. Godinho, P. Gomes, A. Abecasis, A.-M. Vandamme, C. Palma, A. P. Carvalho, J. Cabanas and J. Goncalves. Different substitutions under drug pressure at protease codon 82 in HIV-1 subtype G compared to subtype B infected individuals including a novel I82M resistance mutations [abstract 138]. Antivir Ther. 2005:10;S151.Cane, P. A., A. de Ruiter, P. Rice, M. Wiselka, R. Fox and D. Pillay. 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. 2001:39;2652-2654.PubMed
  • Carrillo, A., K. D. Stewart, H. L. Sham, D. W. Norbeck, W. E. Kohlbrenner, J. M. Leonard, D. J. Kempf and A. Molla. In vitro selection and characterization of human immunodeficiency virus type 1 variants with increased resistance to ABT-378, a novel protease inhibitor. J Virol. 1998:72;7532-7541.PubMed
  • Ceccherini-Silberstein, F., F. Erba, F. Gago, A. Bertoli, F. Forbici, M. C. Bellocchi, C. Gori, R. D'Arrigo, L. Marcon, C. Balotta, A. Antinori, A. D. Monforte and C. F. Perno. Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure. AIDS. 2004:18;F11-19.PubMed
  • Chang, M. W. and B. E. Torbett. Accessory mutations maintain stability in drug-resistant HIV-1 protease. J Mol Biol. 2011:410;756-760.PubMed
  • Clemente, J. C., R. E. Moose, R. Hemrajani, L. R. Whitford, L. Govindasamy, R. Reutzel, R. McKenna, M. Agbandje-McKenna, M. M. Goodenow and B. M. Dunn. Comparing the accumulation of active- and nonactive-site mutations in the HIV-1 protease. Biochemistry. 2004:43;12141-12151.PubMed
  • Colonno, R., R. Rose, C. McLaren, A. Thiry, N. Parkin and J. Friborg. Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. J Infect Dis. 2004:189;1802-1810.PubMed
  • Condra, J. H., D. J. Holder, W. A. Schleif, O. M. Blahy, R. M. Danovich, L. J. Gabryelski, D. J. Graham, D. Laird, J. C. Quintero, A. Rhodes, H. L. Robbins, E. Roth, M. Shivaprakash, T. Yang, J. A. Chodakewitz, P. J. Deutsch, R. Y. Leavitt, F. E. Massari, J. W. Mellors, K. E. Squires, R. T. Steigbigel, H. Teppler and E. A. Emini. Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor. J.Virol. 1996:70;8270-8276.PubMed
  • Condra, J. H., W. A. Schleif, O. M. Blahy, L. J. Gabryelski, D. J. Graham, J. C. Quintero, A. Rhodes, H. L. Robbins, E. Roth and M. Shivaprakash. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature. 1995:374;569-571.PubMed
  • Cote, H. C., Z. L. Brumme and P. R. Harrigan. Human immunodeficiency virus type 1 protease cleavage site mutations associated with protease inhibitor cross-resistance selected by indinavir, ritonavir, and/or saquinavir. J Virol. 2001:75;589-594.PubMed
  • Dauber, D. S., R. Ziermann, N. Parkin, D. J. Maly, S. Mahrus, J. L. Harris, J. A. Ellman, C. Petropoulos and C. S. Craik. Altered substrate specificity of drug-resistant human immunodeficiency virus type 1 protease. J Virol. 2002:76;1359-1368.PubMed
  • De Meyer, S., A. Hill, G. Picchio, R. DeMasi, E. De Paepe and M. P. de Bethune. Influence of baseline protease inhibitor resistance on the efficacy of darunavir/ritonavir or lopinavir/ritonavir in the TITAN trial. J Acquir Immune Defic Syndr. 2008a:49;563-4. PubMed
  • De Meyer, S., T. Vangeneugden, B. van Baelen, E. de Paepe, H. van Marck, G. Picchio, E. Lefebvre and M. P. de Bethune. Resistance profile of darunavir: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses. 2008b:24;379-388.PubMed
  • De Meyer, S., E. Lathouwers, I. Dierynck, E. De Paepe, B. Van Baelen, T. Vangeneugden, S. Spinosa-Guzman, E. Lefebvre, G. Picchio and M. P. de Bethune. Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients. Aids. 2009:23;1829-1840.PubMed
  • Deforche, K., T. Silander, R. Camacho, Z. Grossman, M. A. Soares, K. Van Laethem, R. Kantor, Y. Moreau and A. M. Vandamme. Analysis of HIV-1 pol sequences using Bayesian Networks: implications for drug resistance. Bioinformatics. 2006:22;2975-2979.PubMed
  • Delaugerre, C., J. Pavie, P. Palmer, J. Ghosn, S. Blanche, L. Roudiere, S. Dominguez, E. Mortier, J. M. Molina and P. de Truchis. Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen. AIDS. 2008:22;1809-1813.PubMedPubMed
  • Delaugerre, C., J. Pavie, P. Palmer, J. Ghosn, S. Blanche, L. Roudiere, S. Dominguez, E. Mortier, J. M. Molina and P. de Truchis. Pattern and impact of emerging resistance mutations in treatment experienced patients failing darunavir-containing regimen. AIDS. 2008:22;1809-1813.PubMed
  • Descamps, D., S. Lambert-Niclot, A. G. Marcelin, G. Peytavin, B. Roquebert, C. Katlama, P. Yeni, M. Felices, V. Calvez and F. Brun-Vezinet. Mutations associated with virological response to darunavir/ritonavir in HIV-1-infected protease inhibitor-experienced patients. J Antimicrob Chemother. 2009:63;585-592.PubMed
  • Doyon, L., S. Tremblay, L. Bourgon, E. Wardrop and M. G. Cordingley. Selection and characterization of HIV-1 showing reduced susceptibility to the non-peptidic protease inhibitor tipranavir. Antiviral Res. 2005:68;27-35.PubMed
  • Gatanaga, H., Y. Suzuki, H. Tsang, K. Yoshimura, M. F. Kavlick, K. Nagashima, R. J. Gorelick, S. Mardy, C. Tang, M. F. Summers and H. Mitsuya. 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. 2002:277;5952-5961.PubMed
  • Gong, Y. F., B. S. Robinson, R. E. Rose, C. Deminie, T. P. Spicer, D. Stock, R. J. Colonno and P. F. Lin. In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrob Agents Chemother. 2000:44;2319-2326.PubMed
  • Gonzalez, L. M., R. M. Brindeiro, R. S. Aguiar, H. S. Pereira, C. M. Abreu, M. A. Soares and A. Tanuri. Impact of nelfinavir resistance mutations on in vitro phenotype, fitness, and replication capacity of human immunodeficiency virus type 1 with subtype B and C proteases. Antimicrob Agents Chemother. 2004:48;3552-3555.PubMed
  • Grossman, Z., E. E. Paxinos, D. Averbuch, S. Maayan, N. T. Parkin, D. Engelhard, M. Lorber, V. Istomin, Y. Shaked, E. Mendelson, D. Ram, C. J. Petropoulos and J. M. Schapiro. Mutation D30N is not preferentially selected by human immunodeficiency virus type 1 subtype C in the development of resistance to nelfinavir. Antimicrob Agents Chemother. 2004:48;2159-2165.PubMed
  • Hoffman, N. G., C. A. Schiffer and R. Swanstrom. Covariation of amino acid positions in HIV-1 protease. Virology. 2003:314;536-548.PubMed
  • Jacobsen, H., K. Yasargil, D. L. Winslow, J. C. Craig, A. Krohn, I. B. Duncan and J. Mous. Characterization of human immunodeficiency virus type 1 mutants with decreased sensitivity to proteinase inhibitor Ro 31-8959. Virology. 1995:206;527-534.PubMed
  • Johnston, E., M. A. Winters, S. Y. Rhee, T. C. Merigan, C. A. Schiffer and R. W. Shafer. Association of a novel human immunodeficiency virus type 1 protease substrate cleft mutation, L23I, with protease inhibitor therapy and in vitro drug resistance. Antimicrob Agents Chemother. 2004:48;4864-4868.PubMed
  • Kagan, R. M., P. K. Cheung, T. K. Huard and M. A. Lewinski. Increasing prevalence of HIV-1 protease inhibitor-associated mutations correlates with long-term non-suppressive protease inhibitor treatment. Antiviral Res. 2006:71;42-52.PubMed
  • Kagan, R. M., M. D. Shenderovich, P. N. Heseltine and K. Ramnarayan. Structural analysis of an HIV-1 protease I47A mutant resistant to the protease inhibitor lopinavir. Protein Sci. 2005:14;1870-1878.PubMed
  • Kempf, D. J., J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun and R. A. Rode. Identification of genotypic changes in human immunodeficiency virus protease that correlate with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease inhibitor-experienced patients. J Virol. 2001:75;7462-7469.PubMed
  • Knops, E., I. Kemper, E. Schulter, H. Pfister, R. Kaiser and J. Verheyen. The evolution of protease mutation 76V is associated with protease mutation 46I and gag mutation 431V. AIDS. 2010:24;779-781.PubMed
  • Kolli, M., S. Lastere and C. A. Schiffer. Co-evolution of nelfinavir-resistant HIV-1 protease and the p1-p6 substrate. Virology. 2006:347;405-409.PubMed
  • Kozal, M. J., K. H. Hullsiek, R. Leduc, R. M. Novak, R. D. MacArthur, J. Lawrence and J. D. Baxter. Prevalence and impact of HIV-1 protease codon 33 mutations and polymorphisms in treatment-naive and treatment-experienced patients. Antivir Ther. 2006:11;457-463.PubMed
  • Lambert-Niclot, S., P. Flandre, A. Canestri, G. Peytavin, C. Blanc, R. Agher, C. Soulie, M. Wirden, C. Katlama, V. Calvez and A. G. Marcelin. Factors associated with the selection of mutations conferring resistance to protease inhibitors (PIs) in PI-experienced patients displaying treatment failure on darunavir. Antimicrob Agents Chemother. 2008a:52;491-496.PubMed
  • Lambert-Niclot, S., P. Flandre, I. Malet, A. Canestri, C. Soulie, R. Tubiana, C. Brunet, M. Wirden, C. Katlama, V. Calvez and A. G. Marcelin. Impact of gag mutations on selection of darunavir resistance mutations in HIV-1 protease. J Antimicrob Chemother. 2008b:62;905-908.PubMed
  • Llibre, J. M., J. M. Schapiro and B. Clotet. Clinical implications of genotypic resistance to the newer antiretroviral drugs in HIV-1-infected patients with virological failure. Clin Infect Dis. 2010:50;872-881.PubMed
  • Louis, J. M., Y. Zhang, J. M. Sayer, Y. F. Wang, R. W. Harrison and I. T. Weber. The L76V drug resistance mutation decreases the dimer stability and rate of autoprocessing of HIV-1 protease by reducing internal hydrophobic contacts. Biochemistry. 2011:50;4786-4795.PubMed
  • Maguire, M., D. Shortino, A. Klein, W. Harris, V. Manohitharajah, M. Tisdale, R. Elston, J. Yeo, S. Randall, F. Xu, H. Parker, J. May and W. Snowden. 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. 2002a:46;731-738.PubMed
  • Maguire, M. F., R. Guinea, P. Griffin, S. Macmanus, R. C. Elston, J. Wolfram, N. Richards, M. H. Hanlon, D. J. Porter, T. Wrin, N. Parkin, M. Tisdale, E. Furfine, C. Petropoulos, B. W. Snowden and J. P. Kleim. Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro. J Virol. 2002b:76;7398-7406.PubMed
  • Mahalingam, B., J. M. Louis, J. Hung, R. W. Harrison and I. T. Weber. Structural implications of drug-resistant mutants of HIV-1 protease: high-resolution crystal structures of the mutant protease/substrate analogue complexes. Proteins. 2001:43;455-464.PubMed
  • Malan, D. R., E. Krantz, N. David, V. Wirtz, J. Hammond and D. McGrath. Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr. 2008:47;161-167.PubMed
  • Mammano, F., C. Petit and F. Clavel. 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. 1998:72;7632-7637.PubMed
  • Marcelin, A. G., P. Flandre, J. M. Molina, C. Katlama, P. Yeni, F. Raffi, Z. Antoun, M. Ait-Khaled and V. Calvez. Genotypic resistance analysis of the virological response to fosamprenavir-ritonavir in protease inhibitor-experienced patients in CONTEXT and TRIAD clinical trials. Antimicrob Agents Chemother. 2008:52;4251-4257.PubMed
  • Margerison, E. S., M. Maguire, D. Pillay, P. Cane and R. C. Elston. The HIV-1 protease substitution K55R: a protease-inhibitor-associated substitution involved in restoring viral replication. J Antimicrob Chemother. 2008:61;786-791.PubMed
  • Martinez-Picado, J., A. V. Savara, L. Shi, L. Sutton and R. T. D'Aquila. Fitness of human immunodeficiency virus type 1 protease inhibitor- selected single mutants. Virology. 2000:275;318-322.PubMed
  • Martinez-Picado, J., A. V. Savara, L. Sutton and R. T. D'Aquila. Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1. J.Virol. 1999:73;3744-3752.PubMed
  • Mo, H., N. Parkin, K. D. Stewart, L. Lu, T. Dekhtyar, D. J. Kempf and A. Molla. Identification and structural characterization of I84C and I84A mutations that are associated with high-level resistance to human immunodeficiency virus protease inhibitors and impair viral replication. Antimicrob Agents Chemother. 2007:51;732-735.PubMed
  • Molla, A., M. Korneyeva, Q. Gao, S. Vasavanonda, P. J. Schipper, H. M. Mo, M. Markowitz, T. Chernyavskiy, P. Niu, N. Lyons, A. Hsu, G. R. Granneman, D. D. Ho, C. A. Boucher, J. M. Leonard, D. W. Norbeck and D. J. Kempf. Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med. 1996:2;760-766.PubMed
  • Myint, L., M. Matsuda, Z. Matsuda, Y. Yokomaku, T. Chiba, A. Okano, K. Yamada and W. Sugiura. Gag non-cleavage site mutations contribute to full recovery of viral fitness in protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2004:48;444-452.PubMed
  • Nijhuis, M., R. Schuurman, D. de Jong, J. Erickson, E. Gustchina, J. Albert, P. Schipper, S. Gulnik and C. A. Boucher. Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS. 1999:13;2349-2359.PubMed
  • Nijhuis, M., N. M. van Maarseveen, S. Lastere, P. Schipper, E. Coakley, B. Glass, M. Rovenska, D. de Jong, C. Chappey, I. W. Goedegebuure, G. Heilek-Snyder, D. Dulude, N. Cammack, L. Brakier-Gingras, J. Konvalinka, N. Parkin, H. G. Krausslich, F. Brun-Vezinet and C. A. Boucher. A Novel Substrate-Based HIV-1 Protease Inhibitor Drug Resistance Mechanism. PLoS Med. 2007:4;e36.PubMed
  • Parkin, N. T., C. Chappey and C. J. Petropoulos. Improving lopinavir genotype algorithm through phenotype correlations: novel mutation patterns and amprenavir cross-resistance. AIDS. 2003:17;955-961.PubMed
  • Partaledis, J. A., K. Yamaguchi, M. Tisdale, E. E. Blair, C. Falcione, B. Maschera, R. E. Myers, S. Pazhanisamy, O. Futer, A. B. Cullinan and et al. 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. 1995:69;5228-5235.PubMed
  • Patick, A. K., M. Duran, Y. Cao, D. Shugarts, M. R. Keller, E. Mazabel, M. Knowles, S. Chapman, D. R. Kuritzkes and M. Markowitz. Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir. Antimicrob.Agents Chemother. 1998:42;2637-2644.PubMed
  • Prabu-Jeyabalan, M., E. A. Nalivaika, N. M. King and C. A. Schiffer. Structural basis for coevolution of a human immunodeficiency virus type 1 nucleocapsid-p1 cleavage site with a V82A drug-resistant mutation in viral protease. J Virol. 2004:78;12446-12454.PubMed
  • Quinones-Mateu, M. E., D. M. Moore-Dudley, O. Jegede, J. Weber and J. A. E. Viral drug resistance and fitness. Adv Pharmacol. 2008:56;257-296.PubMed
  • Rhee, S. Y., J. Taylor, W. J. Fessel, D. Kaufman, W. Towner, P. Troia, P. Ruane, J. Hellinger, V. Shirvani, A. Zolopa and R. W. Shafer. HIV-1 protease mutations and protease inhibitor cross-resistance. Antimicrob Agents Chemother. 2010:54;4253-4261.PubMed
  • Schapiro, J. M., J. Lawrence, R. Speck, M. A. Winters, B. Efron, R. W. Coombs, A. C. Collier and T. C. Merigan. Resistance mutations to zidovudine and saquinavir in patients receiving zidovudine plus saquinavir or zidovudine and zalcitabine plus saquinavir in AIDS clinical trials group 229. J Infect Dis. 1999:179;249-253.PubMed
  • Schapiro, J. M., J. Scherer, C. A. Boucher, J. D. Baxter, C. Tilke, C. F. Perno, F. Maggiolo, M. M. Santoro and D. B. Hall. Improving the prediction of virological response to tipranavir: the development and validation of a tipranavir-weighted mutation score. Antivir Ther. 2010:15;1011-1019.PubMed
  • Schock, H. B., V. M. Garsky and L. C. Kuo. Mutational anatomy of an HIV-1 protease variant conferring cross-resistance to protease inhibitors in clinical trials. Compensatory modulations of binding and activity. J Biol Chem. 1996:271;31957-31963.PubMed
  • Scott, W. R. and C. A. Schiffer. Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance. Structure. 2000:8;1259-1265.PubMed
  • Sevin, A. D., V. DeGruttola, M. Nijhuis, J. M. Schapiro, A. S. Foulkes, M. F. Para and C. A. Boucher. Methods for investigation of the relationship between drug- susceptibility phenotype and human immunodeficiency virus type 1 genotype with applications to AIDS clinical trials group 333. J Infect Dis. 2000:182;59-67.PubMed
  • Shahriar, R., S. Y. Rhee, T. F. Liu, W. J. Fessel, A. Scarsella, W. Towner, S. P. Holmes, A. R. Zolopa and R. W. Shafer. Nonpolymorphic human immunodeficiency virus type 1 protease and reverse transcriptase treatment-selected mutations. Antimicrob Agents Chemother. 2009:53;4869-4878.PubMed
  • Sista, P., B. Wasikowski, P. Lecocq, T. Pattery and L. Bacheler. The HIV-1 protease resistance mutation I50L is associated with resistance to atazanavir and susceptibility to other protease inhibitors in multiple mutational contexts. J Clin Virol. 2008:42;405-408.PubMed
  • Svicher, V., F. Ceccherini-Silberstein, F. Erba, M. Santoro, C. Gori, M. C. Bellocchi, S. Giannella, M. P. Trotta, A. Monforte, A. Antinori and C. F. Perno. Novel human immunodeficiency virus type 1 protease mutations potentially involved in resistance to protease inhibitors. Antimicrob Agents Chemother. 2005:49;2015-2025.PubMed
  • Tamiya, S., S. Mardy, M. F. Kavlick, K. Yoshimura and H. Mistuya. Amino acid insertions near Gag cleavage sites restore the otherwise compromised replication of human immunodeficiency virus type 1 variants resistant to protease inhibitors. J Virol. 2004:78;12030-12040.PubMed
  • Van Marck, H., I. Dierynck, G. Kraus, S. Hallenberger, T. Pattery, G. Muyldermans, L. Geeraert, L. Borozdina, R. Bonesteel, C. Aston, E. Shaw, Q. Chen, C. Martinez, V. Koka, J. Lee, E. Chi, M. P. de Bethune and K. Hertogs. The impact of individual human immunodeficiency virus type 1 protease mutations on drug susceptibility is highly influenced by complex interactions with the background protease sequence. J Virol. 2009:83;9512-9520.PubMed
  • Verheyen, J., E. Litau, T. Sing, M. Daumer, M. Balduin, M. Oette, G. Fatkenheuer, J. K. Rockstroh, U. Schuldenzucker, D. Hoffmann, H. Pfister and R. Kaiser. Compensatory mutations at the HIV cleavage sites p7/p1 and p1/p6-gag in therapy-naive and therapy-experienced patients. Antivir Ther. 2006:11;879-887.PubMed
  • Vermeiren, H., E. Van Craenenbroeck, P. Alen, L. Bacheler, G. Picchio and P. Lecocq. Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling. J Virol Methods. 2007:145;47-55.PubMed
  • Weinheimer, S., L. Discotto, J. Friborg, H. Yang and R. Colonno. Atazanavir signature I50L resistance substitution accounts for unique phenotype of increased susceptibility to other protease inhibitors in a variety of human immunodeficiency virus type 1 genetic backbones. Antimicrob Agents Chemother. 2005:49;3816-3824.PubMed
  • Wiesmann, F., J. Vachta, R. Ehret, H. Walter, R. Kaiser, M. Sturmer, A. Tappe, M. Daumer, T. Berg, G. Naeth, P. Braun and H. Knechten. The L76V mutation in HIV-1 protease is potentially associated with hypersusceptibility to protease inhibitors Atazanavir and Saquinavir: is there a clinical advantage? AIDS Res Ther. 2011:8;7.PubMed
  • Wu, T. D., C. A. Schiffer, M. J. Gonzales, J. Taylor, R. Kantor, S. Chou, D. Israelski, A. R. Zolopa, W. J. Fessel and R. W. Shafer. Mutation patterns and structural correlates in human immunodeficiency virus type 1 protease following different protease inhibitor treatments. J Virol. 2003:77;4836-4847.PubMed
  • Zhang, Y. M., H. Imamichi, T. Imamichi, H. C. Lane, J. Falloon, M. B. Vasudevachari and N. P. Salzman. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol. 1997:71;6662-6670.PubMed
  • Ziermann, R., K. Limoli, K. Das, E. Arnold, C. J. Petropoulos and N. T. Parkin. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. J Virol. 2000:74;4414-4419.PubMed

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