Table 2.
Antiviral activity of GRL-04810 and GRL-05010 against multidrug-resistant clinical isolates in PHA-PBMC
| Virus (tropism)a | EC50 (μM)b |
||||||
|---|---|---|---|---|---|---|---|
| SQV | LPV | ATV | APV | DRV | GRL-04810 | GRL-05010 | |
| HIV-1ERS104pre (X4) | 0.0039 ± 0.0001 | 0.033 ± 0.003 | 0.0021 ± 0.0001 | 0.0295 ± 0.0004 | 0.004 ± 0.001 | 0.0023 ± 0.0001 | 0.0027 ± 0.0003 |
| HIV-1MDR/B (X4) | 0.35 (90) ± 0.01 | >1 (>33) | 0.45 (214) ± 0.07 | 0.49 (15) ± 0.05 | 0.021 (5) ± 0.001 | 0.014 (7) ± 0.001 | 0.011 (3) ± 0.001 |
| HIV-1MDR/C (X4) | 0.31 (78) ± 0.02 | >1 (>33) | 0.43 (204) ± 0.01 | 0.21 (7) ± 0.02 | 0.005 (1) ± 0.001 | 0.002 (1) ± 0.001 | 0.002 (1) ± 0.001 |
| HIV-1MDR/G (X4) | 0.039 (10) ± 0.002 | >1 (>33) | 0.042 (19) ± 0.001 | 0.31 (11) ± 0.08 | 0.014 (4) ± 0.009 | 0.004 (2) ± 0.001 | 0.004 (1) ± 0.001 |
| HIV-1MDR/TM (X4) | 0.10 (25) ± 0.04 | >1 (>33) | 0.056 (24) ± 0.007 | 0.328 (12) ± 0.001 | 0.03 (9) ± 0.01 | 0.004 (2) ± 0.001 | 0.004 (2) ± 0.001 |
| HIV-1MDR/JSL (R5) | 0.53 (133) ± 0.01 | >1 (>33) | >1 (>476) | 0.630 (22) ± 0.009 | 0.025 (5) ± 0.002 | 0.021 (10) ± 0.004 | 0.020 (7) ± 0.0002 |
| HIV-1MDR/MM (R5) | 0.11 (27) ± 0.01 | >1 (>33) | 0.081 (38) ± 0.008 | 0.27 (9) ± 0.01 | 0.010 (3) ± 0.001 | 0.002 (1) ± 0.001 | 0.003 (1) ± 0.001 |
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 L90M in HIV-1MDR/G; L10I, K14R, R41K, M46L, I54V, L63P, A71V, V82A, L90M, and I93L in HIV-1MDR/TM; L10I, L24I, I33F, E35D, M36I, N37S, M46L, I54V, R57K, I62V, L63P, A71V, G73S, and V82A in HIV-1MDR/JSL; L10I, K43T, M46L, I54V, L63P, A71V, V82A, L90M, and Q92K in HIV-1MDR/MM. HIV-1ERS104pre served as a source of wild-type HIV-1.
The EC50 values were determined by using PHA-PBMC as target cells, and the inhibition of p24 Gag protein production by each drug was used as an endpoint. The numbers in parentheses represent the fold changes of EC50s for each isolate compared to the EC50s for wild-type HIV-1ERS104pre. All assays were conducted in duplicate or triplicate, and the data shown represent mean values (± 1 standard deviation) derived from the results of three independent experiments. PHA-PBMC were derived from a single donor in each independent experiment.