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Journal of Virology, August 2001, p. 7462-7469, Vol. 75, No. 16
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.
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
*
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.
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