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]