TABLE 2.
Antiviral activities of GRL-98065 against laboratory PI-resistant HIV-1 variantsa
| Virus | Amino acid substitutions in protease-encoding region | EC50 (μM) of drug
|
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| SQV | RTV | IDV | NFV | APV | LPV | ATV | DRV | GRL-98065 | ||
| HIV-1NL4-3 | None (wild type) | 0.007 ± 0.002 | 0.033 ± 0.002 | 0.034 ± 0.004 | 0.033 ± 0.007 | 0.026 ± 0.007 | 0.031 ± 0.009 | 0.0042 ± 0.0004 | 0.0030 ± 0.0001 | 0.0003 ± 0.0002 |
| HIV-1SQV5μM | L10I/G48V/I54V/L63P/A71V/ G73S/V82T | >1 (>143) | >1 (>30) | >1 (>29) | 0.48 ± 0.04 (15) | 0.33 ± 0.03 (13) | 0.27 ± 0.09 (9) | 0.326 ± 0.001 (78) | 0.0058 ± 0.0003 (2) | 0.006 ± 0.003 (20) |
| HIV-1RTV5μM | M46I/V82F/I84V | 0.010 ± 0.008 (1) | >1 (>30) | 0.25 ± 0.01 (7) | 0.21 ± 0.05 (6) | 0.28 ± 0.02 (11) | 0.16 ± 0.02 (5) | 0.018 ± 0.008 (4) | 0.018 ± 0.004 (6) | 0.0025 ± 0.0003 (8) |
| HIV-1IDV5μM | L10F/L24I/M46I/I54V/L63P/A71V/G73S/V82T | 0.059 ± 0.004 (8) | >1 (>30) | >1 (>29) | 0.47 ± 0.07 (14) | 0.17 ± 0.01 (7) | 0.26 ± 0.01 (8) | 0.06 ± 0.02 (14) | 0.015 ± 0.007 (5) | 0.0037 ± 0.0007 (12) |
| HIV-1NFV5μM | L10F/K20T/D30N/K45I/ A71V/V77I | 0.024 ± 0.008 (3) | 0.051 ± 0.005 (2) | 0.27 ± 0.05 (8) | >1 (>30) | 0.060 ± 0.004 (2) | 0.024 ± 0.001 (1) | 0.021 ± 0.006 (5) | 0.0033 ± 0.0001 (1) | 0.0024 ± 0.0008 (8) |
| HIV-1APV5μM | L10F/M46I/I50V/A71V/I84V/L90M | 0.031 ± 0.004 (4) | 0.29 ± 0.02 (9) | 0.200 ± 0.007 (6) | 0.27 ± 0.05 (8) | >1 (>38) | 0.23 ± 0.02 (7) | 0.003 ± 0.001 (1) | 0.33 ± 0.03 (110) | 0.032 ± 0.004 (107) |
| HIV-1LPV1μM | L10F/M46I/I54V/V82A | 0.032 ± 0.002 (5) | >1 (>30) | >1 (>29) | 0.49 ± 0.04 (15) | 0.31 ± 0.02 (12) | 0.31 ± 0.02 (10) | 0.040 ± 0.002 (10) | ND | 0.0075 ± 0.0003 (25) |
| HIV-1ATV1μM | L23I/K43I/M46I/I50L/G51A/A71V | 0.037 ± 0.004 (5) | 0.12 ± 0.06 (4) | 0.388 ± 0.001 (11) | 0.22 ± 0.04 (7) | 0.20 ± 0.07 (8) | 0.033 ± 0.006 (1) | 0.33 ± 0.06 (79) | 0.0034 ± 0.0001 (1) | 0.0015 ± 0.0009 (5) |
| HIV-1GRL98065p20 | A28S/K43I/C67Y/V82I/I85V/L89M | 0.012 ± 0.005 (2) | 0.13 ± 0.05 (4) | 0.04 ± 0.02 (1) | 0.08 ± 0.02 (2) | 0.058 ± 0.009 (2) | 0.034 ± 0.007 (1) | 0.006 ± 0.002 (2) | 0.021 ± 0.009 (7) | 0.0038 ± 0.0006 (13) |
| HIV-1GRL98065p30 | T12I/E21K/A28S/E34K/K43I/M46I/V82I/I85V/L89M | 0.022 ± 0.009 (3) | 0.30 ± 0.03 (9) | 0.059 ± 0.009 (2) | 0.27 ± 0.07 (8) | 0.33 ± 0.09 (13) | 0.06 ± 0.003 (2) | 0.008 ± 0.001 (2) | 0.036 ± 0.001 (12) | 0.008 ± 0.004 (27) |
| HIV-1GRL98065p40 | E21K/A28S/K43I/M46I/I50V/D60N/A71V/V82I/I85V/L89M | 0.032 ± 0.002 (5) | 0.38 ± 0.09 (12) | 0.28 ± 0.02 (8) | 0.34 ± 0.01 (10) | >1 (>38) | 0.19 ± 0.07 (6) | 0.011 ± 0.007 (3) | 0.21 ± 0.03 (70) | 0.18 ± 0.03 (600) |
a
MT-4 cells (104) were exposed to 100 TCID50s of each HIV-1, and inhibition of p24 Gag protein production by each drug was used as an end point. Numbers in parentheses represent n-fold changes in EC50s for each isolate compared to the EC50s for wild-type HIV-1NL4-3. All assays were conducted in duplicate or triplicate, and data shown represent mean values (±1 standard deviation) derived from results of three independent experiments. ND, not determined.