TABLE 1.
Genotypic and phenotypic patterns of virus selected by TMC125 in cultures infected with HIV-1 strains at a high MOIa in the presence of fixed concentrations of TMC125
| Starting virus strain | TMC125 selection concn (nM) | No. of days of selectiona | Amino acid substitution(s) in RTb | Phenotype
|
|||||
|---|---|---|---|---|---|---|---|---|---|
| TMC125
|
Efavirenz
|
Nevirapine
|
|||||||
| Median EC50 (nM) | FCc | Median EC50 (nM) | FC | Median EC50 (nM) | FC | ||||
| LAI | |||||||||
| No selection | 0 | NAd | Wild-type | 1.4 | 1.0 | 1.0 | 1.0 | 76 | 1.0 |
| Expt 1 | 40 | 7 | NTe | NT | NT | NT | NT | NT | NT |
| 200 | 25 | L100L/I, Y181C, T386A | 110 | 78 | 210 | 210 | >10,000 | >130 | |
| Expt 2 | 40 | 11 | V179V/I, Y181C | 7.0 | 5.0 | 1.0 | 1.0 | 6,100 | 80 |
| 200 | No virus breakthrough observed | NA | NA | NA | NA | NA | NA | ||
| Expt 3 | 40 | 13 | Y181C | 6.0 | 5.0 | 1.0 | 1.0 | >10,000 | >130 |
| 200 | No virus breakthrough observed | NA | NA | NA | NA | NA | NA | ||
| SDM-K103N | |||||||||
| No selection | 0 | NA | K103N | 1.1 | 1.0 | 35 | 35 | 3,400 | 45 |
| Expt 1 | 40 | 11 | L100L/I, Y181C/Y | 7.0 | 5.0 | 240 | 240 | >10,000 | >130 |
| 200 | 28 | Y181C, M230M/I | 6.0 | 4.0 | 31 | 31 | >10,000 | >130 | |
| Expt 2 | 40 | 13 | L100L/I, Y181C/Y, Q278R/C | 5.0 | 3.0 | 620 | 620 | >10,000 | >130 |
| 200 | No virus breakthrough observed | ||||||||
| SDM-Y181C | |||||||||
| No selection | 0 | NA | Y181C | 6.9 | 5.0 | 2.0 | 2.0 | >10,000 | >130 |
| Expt 1 | 40 | 7 | V179V/I | 6.7 | 5.0 | 1.1 | 1.0 | 7,600 | 100 |
| 200 | 11 | V179F | 45 | 32 | 2.0 | 2.0 | >10,000 | >130 | |
| Expt 2 | 40 | 9 | V179V/I | 8.4 | 6.0 | 0.9 | 1.0 | 7,600 | 100 |
| 200 | 13 | V179I | 23 | 16 | 1.2 | 1.0 | >10,000 | >130 | |
| SDM-K103N/Y181C | |||||||||
| No selection | 0 | NA | K103N, Y181C | 5.0 | 4.0 | 37 | 37 | >10,000 | >130 |
| Expt 1 | 40 | 7 | E194E/K | 6.3 | 4.0 | 19 | 19 | >10,000 | >130 |
| 200 | 7 | L100I, V189V/I, E194G/E | 83 | 59 | 1,400 | 1,400 | >10,000 | >130 | |
| 1,000 | 11 | L100I, E194G | 540 | 390 | 6,000 | 6,000 | >10,000 | >130 | |
| Expt 2 | 40 | 6 | P313P/S | 3.9 | 3.0 | 24 | 24 | >10,000 | >130 |
| 200 | 9 | L100I, V189V/I, E194G/E, R356R/K | 17 | 12 | 21 | 21 | >10,000 | >130 | |
| 1,000 | 13 | L100I, V189I, E194G | 230 | 160 | 5,800 | 5,800 | >10,000 | >130 | |
Virus supernatant was harvested and used for genotypic and phenotypic analysis when there was 100% virus breakthrough as described in Materials and Methods. For full details of time to virus breakthrough for concentrations of inhibitor of 40 nM to 1.0 μM, refer to Fig. 1 and 2.
Amino acid substitutions are reported as changes compared with the wild-type HIV-1 (clone HXB2) reference sequence. For selections starting from SDMs, only additional mutations acquired during selection are given.
Calculated as the median EC50 for the selected virus strain divided by the median EC50 of wild-type HIV-1.
NA, not applicable.
NT, not tested.