Table 5.
Relative in vitro replication capacity of NS3 variants
| Variant | Telaprevir replicon EC50 fold changea | Level of resistance to telaprevirb | Replication capacity ± SD (%)c |
|---|---|---|---|
| WT | 1 | None | 100 ± 7 |
| V36I | 0.3 | 146 ± 18 | |
| V36A | 7.4 | Lower | 104 ± 26 |
| V36C | 7.8 | 98 ± 9 | |
| V36G | 11 | 59 ± 8 | |
| V36M | 7.0 | 77 ± 12 | |
| T54A | 6.3 | 65 ± 10 | |
| T54S | 4.2 | 59 ± 3 | |
| R155G | 7.4 | 10 ± 3 | |
| R155I | 24 | 20 ± 7 | |
| R155K | 7.4 | 80 ± 16 | |
| R155M | 5.6 | 18 ± 2 | |
| R155S | 4.1 | 45 ± 8 | |
| R155T | 20 | 39 ± 7 | |
| A156S | 9.6 | 88 ± 8 | |
| V36A + T54A | 20 | 8 ± 2 | |
| A156N | >93 | Higher | 9 ± 4 |
| A156T | >62 | 16 ± 2 | |
| A156V | >62 | 9 ± 2 | |
| V36A + R155K | ∼41 | 57 ± 4 | |
| V36A + R155T | >62 | 23 ± 11 | |
| V36M + R155K | ∼64 | 42 ± 6 | |
| V36M + R155T | >62 | 36 ± 8 | |
| V36M + A156T | >62 | 9 ± 5 |
The fold change of the mean EC50 of the variant replicon compared with that of the WT replicon was determined in G1b 48-h or 96-h assays as presented in Table 1. “>” and “∼” are as described in Table 1.
Lower-level resistance, EC50 change from 3- to 25-fold; higher-level resistance, EC50 change > 25-fold. V36I did not confer resistance to telaprevir (EC50 change < 3-fold).
The mean replication capacity and SD were derived from 31 and 3 to 7 individual experiments for the WT and variant replicons, respectively. Data for V36I, T54S, A156N, and A156S were generated with a pFK I341PiLuc/NS3-3′/ET replicon in Huh-7-ET-cured cells; the rest of the data were generated with a pBR322-Luc-mADE replicon in Huh-7.5 cells.