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. 2000 Sep;44(9):2319-26.
doi: 10.1128/AAC.44.9.2319-2326.2000.

In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632

Y F Gong  1 , B S Robinson, R E Rose, C Deminie, T P Spicer, D Stock, R J Colonno, P F Lin
Affiliations

In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632

Y F Gong et al. Antimicrob Agents Chemother. 2000 Sep.

Abstract

BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC(50)], 2.6 to 5.3 nM; EC(90), 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0. 1- to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir- and ritonavir-resistant viruses displayed six- to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy.

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Figures

FIG. 1
FIG. 1
Chemical structure of BMS-232632.
FIG. 2
FIG. 2
Appearance of amino acid substitutions in HIV-1 RF. Eleven to 32 Prt clones were sequenced for each of the provirus populations treated with BMS-232632 at 0, 25, 60, 100, 150, 200, 250, and 500 nM as described in Materials and Methods. Lines represent the percentage of sequenced clones containing N88S (□), M46I (■), A71V (▵), V32I (▴), L33F (⧫) or I84V (○) amino acid substitutions independent of whether multiple changes occurred within a given clone.
FIG. 3
FIG. 3
Appearance of amino acid substitutions in HIV-1 BRU. Twelve to 28 Prt clones were sequenced for each of the provirus populations treated with BMS-232632 at 0, 10, 14, 20, 28, 75, 200, and 500 nM as described in Materials and Methods. Lines represent the percentage of sequenced clones containing N88S (□), I50L (■), L10Y/F (▵), A71V (▴), or L63P (⧫) amino acid substitutions independent of whether multiple changes occurred within a given clone.
FIG. 4
FIG. 4
Appearance of amino acid substitutions in HIV-1 NL4-3. Twelve to 32 Prt clones were sequenced for each of the provirus populations treated with BMS-232632 at 0, 10, 12, 15, 20, 40 and 200 nM as described in Materials and Methods. Lines represent the percentage of sequenced clones containing L23I (□), M46I/L (■), I84V (▵), V32I (◊), M89L (⧫), A71V (▴), or L10Y (○) amino acid substitutions independent of whether multiple changes occurred within a given clone.
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