TABLE 3.
Activities of GRL-216 and GRL-286 against multi-drug-resistant clinical isolates in PHA-PBMsa
| Virus (syncytium formation) | EC50 (μM) |
||||||||
|---|---|---|---|---|---|---|---|---|---|
| SQV | IDV | APV | LPV | AZV | TPV | DRV | GRL-216 | GRL-286 | |
| HIV-1ERS104 pre (wild type; SI) | 0.008 ± 0.005 | 0.043 ± 0.004 | 0.030 ± 0.005 | 0.034 ± 0.002 | 0.002 ± 0.001 | 0.12 ± 0.03 | 0.003 ± 0.0002 | 0.005 ± 0.003 | 0.007 ± 0.002 |
| HIV-1MDR/B (SI) | 0.27 ± 0.073 (34) | >1 (>23) | >1 (>33) | >1 (>29) | 0.20 ± 0.10 (100) | 0.18 ± 0.009 (2) | 0.019 ± 0.012 (6) | 0.037 ± 0.016 (7) | 0.089 ± 0.016 (13) |
| HIV-1MDR/C (SI) | 0.032 ± 0.002 (11) | >1 (>23) | 0.37 ± 0.011 (12) | >1 (>29) | 0.065 ± 0.008 (33) | 0.38 ± 0.079 (3) | 0.008 ± 0.006 (3) | 0.044 ± 0.002 (9) | 0.029 ± 0.001 (4) |
| HIV-1MDR/G (SI) | 0.030 ± 0.002 (4) | 0.34 ± 0.14 (5) | 0.43 ± 0.004 (14) | 0.26 ± 0.04 (8) | 0.033 ± 0.024 (17) | 0.24 ± 0.08 (2) | 0.023 ± 0.006 (5) | 0.057 ± 0.012 (11) | 0.028 ± 0.004 (4) |
| HIV-1MDR/TM (SI) | 0.26 ± 0.04 (33) | >1 (>23) | 0.32 ± 0.007 (11) | >1 (>29) | 0.065 ± 0.008 (33) | 0.38 ± 0.05 (3) | 0.004 ± 0.001 (1) | 0.027 ± 0.001 (6) | 0.072 ± 0.014 (10) |
| HIV-1MDR/MM (NSI) | 0.19 ± 0.05 (24) | >1 (>23) | 0.21 ± 0.222 (7) | >1 (>29) | 0.18 ± 0.021 (89) | 0.35 ± 0.06 (3) | 0.011 ± 0.002 (4) | 0.033 ± 0.010 (7) | 0.055 ± 0.025 (8) |
| HIV-1MDR/JSL (NSI) | 0.30 ± 0.02 (37) | >1 (>23) | 0.62 ± 0.02 (21) | >1 (>29) | 0.43 ± 00.036 (215) | 0.23 ± 0.049 (2) | 0.027 ± 0.011 (9) | 0.073 ± 0.07 (15) | 0.21 ± 0.032 (30) |
The amino acid substitutions identified in the protease-encoding region compared to the consensus type B sequence cited from the Los Alamos database include L63P in HIV-1ERS104pre; L10I, K14R, L33I, M36I, M46I, F53I, K55R, I62V, L63P, A71V, G73S, V82A, L90M, and I93L in HIV-1MDR/B; L10I, I15V, K20R, L24I, M36I, M46L, I54V, I62V, L63P, K70Q, V82A, and L89M in HIV-1MDR/C; L10I, V11I, T12E, I15V, L19I, R41K, M46L, L63P, A71T, V82A, and L90 M in HIV-1MDR/G; L10I, K14R, R41K, M46L, I54V, L63P, A71V, V82A, L90M, and I93L in HIV-1MDR/TM; L10I, K43T, M46L, I54V, L63P, A71V, V82A, L90M, and Q92K in HIV-1MDR/MM; and L10I, L24I, I33F, E35D, M36I, N37S, M46L, I54V, R57K, I62V, L63P, A71V, G73S, and V82A in HIV-1MDR/JSL. HIV-1ERS104pre served as a source of wild-type HIV-1. EC50s were determined by using PHA-PBMCs as target cells, and inhibition of p24 Gag protein production by each drug was used as the end point. Numbers in parentheses represent the n-fold changes in the EC50s for each isolate compared to the EC50s for wild-type isolate HIV-1ERS104pre. All assays were conducted in duplicate or triplicate, and the data shown represent the mean values (±1 standard deviation) derived from results of three independent experiments.