This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kempf, D. J.
Right arrow Articles by Rode, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kempf, D. J.
Right arrow Articles by Rode, R. A.

 Previous Article  |  Next Article 

Journal of Virology, August 2001, p. 7462-7469, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7462-7469.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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

Dale J. Kempf,* Jeffrey D. Isaacson, Martin S. King, Scott C. Brun, Yi Xu, Kathryn Real, Barry M. Bernstein, Anthony J. Japour, Eugene Sun, and Richard A. Rode

Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064

Received 8 January 2001/Accepted 15 May 2001

The association of genotypic changes in human immunodeficiency virus (HIV) protease with reduced in vitro susceptibility to the new protease inhibitor lopinavir (previously ABT-378) was explored using a panel of viral isolates from subjects failing therapy with other protease inhibitors. Two statistical tests showed that specific mutations at 11 amino acid positions in protease (L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, and L90M) were associated with reduced susceptibility. Mutations at positions 82, 54, 10, 63, 71, and 84 were most closely associated with relatively modest (4- and 10-fold) changes in phenotype, while the K20M/R and F53L mutations, in conjunction with multiple other mutations, were associated with >20- and >40-fold-reduced susceptibility, respectively. The median 50% inhibitory concentrations (IC50) of lopinavir against isolates with 0 to 3, 4 or 5, 6 or 7, and 8 to 10 of the above 11 mutations were 0.8-, 2.7-, 13.5-, and 44.0-fold higher, respectively, than the IC50 against wild-type HIV. On average, the IC50 of lopinavir increased by 1.74-fold per mutation in isolates containing three or more mutations. Each of the 16 viruses that displayed a >20-fold change in susceptibility contained mutations at residues 10, 54, 63, and 82 and/or 84, along with a median of three mutations at residues 20, 24, 46, 53, 71, and 90. The number of protease mutations from the 11 identified in these analyses (the lopinavir mutation score) may be useful for the interpretation of HIV genotypic resistance testing with respect to lopinavir-ritonavir (Kaletra) regimens and may provide insight into the genetic barrier to resistance to lopinavir-ritonavir in both antiretroviral therapy-naive and protease inhibitor-experienced patients.

* Corresponding author. Mailing address: D-47D, AP52, Abbott Laboratories, 200 Abbott Park Rd., Abbott Park, IL 60064. Phone: (847) 937-0324. Fax: (847) 938-2756. E-mail: dale.kempf{at}abbott.com.

Journal of Virology, August 2001, p. 7462-7469, Vol. 75, No. 16
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.16.7462-7469.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Molina, J.-M., Ait-Khaled, M., Rinaldi, R., Penco, G., Baril, J.-G., Cauda, R., Soriano, V., Pialoux, G., Wire, M. B., Lou, Y., Givens, N., Craig, C., Nichols, W. G., Barbosa, I., Yeo, J., on behalf of the TRIAD Study Group, (2009). Fosamprenavir/ritonavir in advanced HIV disease (TRIAD): a randomized study of high-dose, dual-boosted or standard dose fosamprenavir/ritonavir in HIV-1-infected patients with antiretroviral resistance. J Antimicrob Chemother 64: 398-410 [Abstract] [Full Text]  
  • Khanlou, H., Sayana, S., Acosta, E. (2008). No Residual Activity of Raltegravir After Development of 148 Complex Mutations In Vivo. J Int Assoc Physicians AIDS Care (Chic Ill) 7: 281-282  
  • Grant, P., Wong, E. C., Rode, R., Shafer, R., De Luca, A., Nadler, J., Hawkins, T., Cohen, C., Harrington, R., Kempf, D., Zolopa, A. (2008). Virologic Response to Lopinavir-Ritonavir-Based Antiretroviral Regimens in a Multicenter International Clinical Cohort: Comparison of Genotypic Interpretation Scores. Antimicrob. Agents Chemother. 52: 4050-4056 [Abstract] [Full Text]  
  • Dekhtyar, T., Ng, T. I., Lu, L., Masse, S., DeGoey, D. A., Flosi, W. J., Grampovnik, D. J., Klein, L. L., Kempf, D. J., Molla, A. (2008). Characterization of a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, A-790742. Antimicrob. Agents Chemother. 52: 1337-1344 [Abstract] [Full Text]  
  • Lambert-Niclot, S., Flandre, P., Canestri, A., Peytavin, G., Blanc, C., Agher, R., Soulie, C., Wirden, M., Katlama, C., Calvez, V., Marcelin, A.-G. (2008). 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. 52: 491-496 [Abstract] [Full Text]  
  • Larru, B., Resino, S., Bellon, J. M., de Jose, M. I., Fortuny, C., Navarro, M. L., Gurbindo, M. D., Ramos, J. T., Soler Palacin, P., Leon, J. A., Asensi, M., Mellado, M. J., Munoz-Fernandez, M. A. (2008). Long-term response to highly active antiretroviral therapy with lopinavir/ritonavir in pre-treated vertically HIV-infected children. J Antimicrob Chemother 61: 183-190 [Abstract] [Full Text]  
  • King, M. S., Rode, R., Cohen-Codar, I., Calvez, V., Marcelin, A.-G., Hanna, G. J., Kempf, D. J. (2007). Predictive Genotypic Algorithm for Virologic Response to Lopinavir-Ritonavir in Protease Inhibitor-Experienced Patients. Antimicrob. Agents Chemother. 51: 3067-3074 [Abstract] [Full Text]  
  • Mo, H., Parkin, N., Stewart, K. D., Lu, L., Dekhtyar, T., Kempf, D. J., Molla, A. (2007). 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. 51: 732-735 [Abstract] [Full Text]  
  • Yates, P. J., Hazen, R., St. Clair, M., Boone, L., Tisdale, M., Elston, R. C. (2006). In Vitro Development of Resistance to Human Immunodeficiency Virus Protease Inhibitor GW640385. Antimicrob. Agents Chemother. 50: 1092-1095 [Abstract] [Full Text]  
  • Jimenez, J. L., Resino, S., Martinez-Colom, A., Bellon, J. M., Angeles Munoz-Fernandez, M., on behalf of the Spanish Group of Paediatric HIV I, (2005). Mutations at codons 54 and 82 of HIV protease predict virological response of HIV-infected children on salvage lopinavir/ritonavir therapy. J Antimicrob Chemother 56: 1081-1086 [Abstract] [Full Text]  
  • Weinheimer, S., Discotto, L., Friborg, J., Yang, H., Colonno, R. (2005). 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. 49: 3816-3824 [Abstract] [Full Text]  
  • Stratov, I., Dale, C. J., Chea, S., McCluskey, J., Kent, S. J. (2005). Induction of T-Cell Immunity to Antiretroviral Drug-Resistant Human Immunodeficiency Virus Type 1. J. Virol. 79: 7728-7737 [Abstract] [Full Text]  
  • Marcelin, A.-G., Cohen-Codar, I., King, M. S., Colson, P., Guillevic, E., Descamps, D., Lamotte, C., Schneider, V., Ritter, J., Segondy, M., Peigue-Lafeuille, H., Morand-Joubert, L., Schmuck, A., Ruffault, A., Palmer, P., Chaix, M.-L., Mackiewicz, V., Brodard, V., Izopet, J., Cottalorda, J., Kohli, E., Chauvin, J.-P., Kempf, D. J., Peytavin, G., Calvez, V. (2005). Virological and Pharmacological Parameters Predicting the Response to Lopinavir-Ritonavir in Heavily Protease Inhibitor-Experienced Patients. Antimicrob. Agents Chemother. 49: 1720-1726 [Abstract] [Full Text]  
  • Svicher, V., Ceccherini-Silberstein, F., Erba, F., Santoro, M., Gori, C., Bellocchi, M. C., Giannella, S., Trotta, M. P., Monforte, A. d., Antinori, A., Perno, C. F. (2005). Novel Human Immunodeficiency Virus Type 1 Protease Mutations Potentially Involved in Resistance to Protease Inhibitors. Antimicrob. Agents Chemother. 49: 2015-2025 [Abstract] [Full Text]  
  • Mo, H., King, M. S., King, K., Molla, A., Brun, S., Kempf, D. J. (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: 3329-3338 [Abstract] [Full Text]  
  • Resino, S., Bellon, J. M., Ramos, J. T., Gonzalez-Rivera, M., de Jose, M. I., Gonzalez, M. I., Gurbindo, D., Mellado, M. J., Cabrero, E., Munoz-Fernandez, M. A. (2004). Positive virological outcome after lopinavir/ritonavir salvage therapy in protease inhibitor-experienced HIV-1-infected children: a prospective cohort study. J Antimicrob Chemother 54: 921-931 [Abstract] [Full Text]  
  • Chen, L., Perlina, A., Lee, C. J. (2004). Positive Selection Detection in 40,000 Human Immunodeficiency Virus (HIV) Type 1 Sequences Automatically Identifies Drug Resistance and Positive Fitness Mutations in HIV Protease and Reverse Transcriptase. J. Virol. 78: 3722-3732 [Abstract] [Full Text]  
  • Rhodes, T., Wargo, H., Hu, W.-S. (2003). High Rates of Human Immunodeficiency Virus Type 1 Recombination: Near-Random Segregation of Markers One Kilobase Apart in One Round of Viral Replication. J. Virol. 77: 11193-11200 [Abstract] [Full Text]  
  • 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: 319-323 [Full Text]  
  • Wu, T. D., Schiffer, C. A., Gonzales, M. J., Taylor, J., Kantor, R., Chou, S., Israelski, D., Zolopa, A. R., Fessel, W. J., Shafer, R. W. (2003). Mutation Patterns and Structural Correlates in Human Immunodeficiency Virus Type 1 Protease following Different Protease Inhibitor Treatments. J. Virol. 77: 4836-4847 [Abstract] [Full Text]  
  • Colonno, R. J., Thiry, A., Limoli, K., Parkin, N. (2003). Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors. Antimicrob. Agents Chemother. 47: 1324-1333 [Abstract] [Full Text]  
  • Watkins, T., Resch, W., Irlbeck, D., Swanstrom, R. (2003). Selection of High-Level Resistance to Human Immunodeficiency Virus Type 1 Protease Inhibitors. Antimicrob. Agents Chemother. 47: 759-769 [Abstract] [Full Text]  
  • Hsu, A., Isaacson, J., Brun, S., Bernstein, B., Lam, W., Bertz, R., Foit, C., Rynkiewicz, K., Richards, B., King, M., Rode, R., Kempf, D. J., Granneman, G. R., Sun, E. (2003). Pharmacokinetic-Pharmacodynamic Analysis of Lopinavir-Ritonavir in Combination with Efavirenz and Two Nucleoside Reverse Transcriptase Inhibitors in Extensively Pretreated Human Immunodeficiency Virus-Infected Patients. Antimicrob. Agents Chemother. 47: 350-359 [Abstract] [Full Text]  
  • Matsuoka-Aizawa, S., Sato, H., Hachiya, A., Tsuchiya, K., Takebe, Y., Gatanaga, H., Kimura, S., Oka, S. (2002). Isolation and Molecular Characterization of a Nelfinavir (NFV)-Resistant Human Immunodeficiency Virus Type 1 That Exhibits NFV-Dependent Enhancement of Replication. J. Virol. 77: 318-327 [Abstract] [Full Text]  
  • Masquelier, B., Breilh, D., Neau, D., Lawson-Ayayi, S., Lavignolle, V., Ragnaud, J.-M., Dupon, M., Morlat, P., Dabis, F., Fleury, H. (2002). Human Immunodeficiency Virus Type 1 Genotypic and Pharmacokinetic Determinants of the Virological Response to Lopinavir-Ritonavir-Containing Therapy in Protease Inhibitor-Experienced Patients. Antimicrob. Agents Chemother. 46: 2926-2932 [Abstract] [Full Text]  
  • Molla, A., Mo, H., Vasavanonda, S., Han, L., Lin, C. T., Hsu, A., Kempf, D. J. (2002). In Vitro Antiviral Interaction of Lopinavir with Other Protease Inhibitors. Antimicrob. Agents Chemother. 46: 2249-2253 [Abstract] [Full Text]  
  • Shafer, R. W. (2002). Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance. Clin. Microbiol. Rev. 15: 247-277 [Abstract] [Full Text]  
  • Kantor, R., Fessel, W. J., Zolopa, A. R., Israelski, D., Shulman, N., Montoya, J. G., Harbour, M., Schapiro, J. M., Shafer, R. W. (2002). Evolution of Primary Protease Inhibitor Resistance Mutations during Protease Inhibitor Salvage Therapy. Antimicrob. Agents Chemother. 46: 1086-1092 [Abstract] [Full Text]  
  • Beck, I. A., Mahalanabis, M., Pepper, G., Wright, A., Hamilton, S., Langston, E., Frenkel, L. M. (2002). Rapid and Sensitive Oligonucleotide Ligation Assay for Detection of Mutations in Human Immunodeficiency Virus Type 1 Associated with High-Level Resistance to Protease Inhibitors. J. Clin. Microbiol. 40: 1413-1419 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»