TABLE 1.
Selection conditions and genotypic analyses
| Selecting drug(s) | Culture name | Starting conditions
|
First detection of genotypic resistance
|
Ending conditions
|
Comment | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Concn (μM [fold over EC50])a,b | Starting virus | Genotypec | Time (days) | Concn (μM [fold over EC50])a | Genotypec | Duration (days) | Concn (μM [fold over EC50])a | Genotypec | |||
| FTC | F1 | 0.8 (1) | IIIb | wt | 14 | 0.8 (1) | M184I/M/V | 48 | 230 (288) | M184V/I | Strong viral growth |
| FTC | F2 | 0.8 (1) | LAI | wt | 18 | 3.2 (4) | M184I/M | 58 | 230 (288) | M184V | Strong viral growth |
| 3TC | 3 | 4 (1) | LAI | wt | 11 | 4 (1) | M184I/M | 58 | 512 (128) | M184I | Strong viral growth |
| TFV | T1 | 3.5 (1) | IIIb | wt | 56 | 56 (16) | K65R | 99 | 112 (32) | K65R | Weak viral growth |
| TFV | T2 | 3.5 (1) | LAI | wt | 44 | 28 (8) | K65R/K | 328 | 168 (48) | K65R S68K H221Y | Weak viral growth |
| ABC | A | 0.4 (1) | LAI | wt | 44 | 6.4 (16) | M184I | 203 | 51.2 (128) | K65R Y115F M184V H221Y | Strong viral growth |
| FTC-TFV | FT1 | 0.4 (1/2), 1.75 (1/2) | IIIb | wt | 24 | 1.6 (2), 7 (2) | M184I/M | 133 | 12.8 (16), 56 (16) | K65R | Weak viral growth |
| FTC-TFV | FT2 | 0.4 (1/2), 1.75 (1/2) | LAI | wt | 40 | 1.6 (2), 7 (2) | M184I/M | 288 | 25.6 (32), 112 (32) | K65N K70Rg | Transition from intermediate K65R to K65N+K70R genotype (∼day 130) |
| FTC-TFV | FT3d | 1.8 (2.3), 0.25 (0.07) | LAI | wt | 18 | 1.8 (2.3), 0.25 (0.07) | M184I | 71 | 230 (288), 32 (9) | K65R M184V | Starting concentrations based on Cmax for each drug |
| FTC-TFV | FT1ae | 51.2 (64), 7 (2) | IIIb | M184I L214F | NAf | 42 | 51.2 (64), 28 (8) | K65R M184I L214F | [FTC] kept constant | ||
| FTC-TFV | FT1be | 25.6 (32), 28 (8) | IIIb | K65R | NA | 54 | 230 (288), 28 (8) | K65R M184V | [TFV] kept constant | ||
| 3TC-ABC | 3A | 2 (1/2), 0.2 (1/2) | LAI | wt | 18 | 2 (1/2), 0.2 (1/2) | M184I/M | 329 | 512 (128), 51.2 (128) | L74V Q161L M184V T200A H221Y | Strong viral growth |
Concentrations are shown in the same order as the selecting drugs. Expressed in μM.
Selections from wild-type virus were started at EC50 for single selections and at one-half the EC50 for each drug in dual selections, with the exception of the FT3 culture.
Genotypic analyses of the selected viruses captured the first 300 amino acids of RT. wt, wild type.
In the FT3 culture, starting concentrations were one-fourth the Cmax of each drug: FTC Cmax = 7.2 μM; TFV Cmax = 1 μM.
Both FT1a and FT1b were started from viral harvests obtained from culture FT1 that had genotypic resistance.
NA, not applicable.
Further selection at higher FTC concentration (32-fold EC50 for TFV and 128-fold EC50 for FTC) gave rise to a virus population with A62V + K65R + M184V.