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

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 isolate s from subjects failing therapy with other protease inhibitors. Two statist ical tests showed that specific mutations at 11 amino acid positions in pro tease (L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, 184V, and L90M) were associated with reduced susceptibility. Muta tions 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 K20 M/R and F53L mutations, in conjunction with multiple other mutations, were associated with > 20- and > 40-fold-reduced susceptibility, respectively. T he median 50% inhibitory concentrations (IC50) of lopinavir against isolate s 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 pe r mutation in isolates containing three or more mutations. Each of the 16 v iruses that displayed a > 20-fold change in susceptibility contained mutati ons 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 mu tations from the 11 identified in these analyses (the lopinavir mutation sc ore) may be useful for the interpretation of HIV genotypic resistance testi ng with respect to lopinavir-ritonavir (Kaletra) regimens and may provide i nsight into the genetic barrier to resistance to lopinavir-ritonavir in bot h antiretroviral therapy-naive and protease inhibitor-experienced patients.