TABLE 3.
Antiviral activities of GRL-98065 against multidrug-resistant clinical isolates and various subtypes in PHA-PBMs
| Virusa | EC50 (μM)
|
||||||||
|---|---|---|---|---|---|---|---|---|---|
| SQV | RTV | IDV | NFV | APV | LPV | ATV | DRV | GRL-98065 | |
| HIV-1ERS104pre (wild type: X4) | 0.008 ± 0.003 | 0.025 ± 0.005 | 0.024 ± 0.008 | 0.015 ± 0.004 | 0.029 ± 0.005 | 0.007 ± 0.001 | 0.0038 ± 0.0004 | 0.0038 ± 0.0007 | 0.0005 ± 0.0002 |
| HIV-1MDR/TM (X4) | 0.18 ± 0.05 (23) | >1 (>40) | >1 (>42) | >1 (>67) | 0.30 ± 0.04 (10) | 0.36 ± 0.09 (51) | 0.038 ± 0.009 (10) | 0.0043 ± 0.0007 (1) | 0.0032 ± 0.0006 (6) |
| HIV-1MDR/MM (R5) | 0.14 ± 0.04 (18) | >1 (>40) | >1 (>42) | >1 (>67) | 0.48 ± 0.09 (17) | 0.38 ± 0.08 (54) | 0.045 ± 0.0001 (12) | 0.016 ± 0.007 (4) | 0.0038 ± 0.0006 (8) |
| HIV-1MDR/JSL (R5) | 0.29 ± 0.05 (36) | >1 (>40) | >1 (>42) | >1 (>67) | 0.43 ± 0.05 (15) | 0.70 ± 0.19 (100) | 0.54 ± 0.20 (142) | 0.027 ± 0.009 (7) | 0.006 ± 0.002 (12) |
| HIV-1MDR/B (X4) | 0.27 ± 0.06 (34) | >1 (>40) | >1 (>42) | >1 (>67) | 0.36 ± 0.09 (12) | 0.30 ± 0.03 (43) | 0.25 ± 0.003 (66) | 0.04 ± 0.01 (11) | 0.0039 ± 0.0005 (8) |
| HIV-1MDR/C (X4) | 0.035 ± 0.004 (4) | >1 (>40) | >1 (>42) | 0.42 ± 0.06 (28) | 0.25 ± 0.05 (9) | 0.31 ± 0.05 (44) | 0.021 ± 0.006 (6) | 0.009 ± 0.005 (2) | 0.0027 ± 0.0003 (5) |
| HIV-1MDR/G (X4) | 0.033 ± 0.005 (4) | >1 (>40) | 0.64 ± 0.11 (27) | 0.37 ± 0.05 (25) | 0.32 ± 0.02 (11) | 0.16 ± 0.04 (23) | 0.032 ± 0.002 (8) | 0.007 ± 0.005 (2) | 0.0034 ± 0.0003 (7) |
| HIV-192UG029 (subtype A: X4) | 0.0048 ± 0.0005 | 0.071 ± 0.011 | 0.044 ± 0.009 | 0.043 ± 0.006 | 0.046 ± 0.006 | 0.007 ± 0.001 | 0.006 ± 0.002 | ND | 0.0005 ± 0.0002 |
| HIV-192UG037 (subtype A: R5) | 0.0032 ± 0.0003 | 0.041 ± 0.008 | 0.034 ± 0.003 | 0.056 ± 0.014 | 0.027 ± 0.005 | 0.005 ± 0.001 | 0.0025 ± 0.0002 | ND | 0.0004 ± 0.0001 |
| HIV-1Ba-L (subtype B: R5) | 0.0083 ± 0.0005 | 0.023 ± 0.006 | 0.022 ± 0.005 | 0.018 ± 0.004 | 0.025 ± 0.006 | 0.0053 ± 0.0004 | 0.0013 ± 0.0004 | ND | 0.0002 ± 0.0001 |
| HIV-197ZA003 (subtype C: R5) | 0.0067 ± 0.0008 | 0.039 ± 0.004 | 0.037 ± 0.006 | 0.037 ± 0.007 | 0.033 ± 0.005 | 0.0073 ± 0.0006 | 0.0034 ± 0.0001 | ND | 0.0005 ± 0.0001 |
| HIV-192TH019 (subtype E: R5) | 0.0030 ± 0.0001 | 0.030 ± 0.009 | 0.021 ± 0.001 | 0.029 ± 0.004 | 0.021 ± 0.006 | 0.0033 ± 0.0005 | 0.0027 ± 0.0001 | ND | 0.0003 ± 0.0001 |
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, R41K, M46L, I54V, L63P, A71V, V82A, L90M, I93L in HIV-1MDR/TM; L10I, K43T, M46L, I54V, L63P, A71V, V82A, L90M, and Q92K in HIV-1 MDR/MM; L10I, L24I, I33F, E35D, M36I, N37S, M46L, I54V, R57K, I62V, L63P, A71V, G73S, and V82A in HIV-1 MDR/JSL; L10I, K14R, L33I, M36I, M46I, F53I, K55R, I62V, L63P, A71V, G73S, V82A, L90M, and I93L in HIV-1 MDR/B; L10I, I15V, K20R, L24I, M36I, M46L, I54V, I62V, L63P, K70Q,V82A, and L89M in HIV-1 MDR/C; and L10I, V11I, T12E, I15V, L19I, R41K, M46L, L63P, A71T, V82A, and L90M in HIV-1 MDR/G. HIV-1ERS104pre served as a source of wild-type HIV-1. EC50s were determined by using PHA-PBMs as target cells, and inhibition of p24 Gag protein production by each drug was used as an end point. Numbers in parentheses represent n-fold changes of EC50s for each isolate compared to EC50s for wild-type HIV-1ERS104pre. All assays were conducted in duplicate or triplicate, and data shown represent mean values (±1 standard deviation) derived from results of three independent experiments. PHA-PBMs were derived from a single donor in each independent experiment. ND, not determined.