TABLE 3.
Susceptibilities of HIV-1 IN recombinant molecular clonesa
| Molecular clone(s) | Mean EC50 (nM) ± SD (fold resistance compared to wild type)
|
||||
|---|---|---|---|---|---|
| AZT | EVG | L-870,810 | S-1360 | L-731,988 | |
| HIV-1WT | 32 | 1.1 | 5.8 | 1,239 | 736 |
| EVG mutation (expt 1)b | |||||
| T66Ic | 43 ± 11 (1.3) | 41 ± 14 (37) | 4.7 ± 2.9 (0.8) | 6,403 ± 2,349 (5.2) | 7,234 ± 1,210 (9.8) |
| Q95K | 34 ± 6 (1.1) | 2.9 ± 0.4 (2.6) | 18 ± 2 (3.1) | ND | ND |
| E138K | 33 ± 8 (1.0) | 1.1 ± 0.4 (1.0) | 3.9 ± 0.4 (0.7) | ND | ND |
| Q146P | 26 ± 2 (0.8) | 12 ± 3 (11) | 5.1 ± 0.4 (0.9) | ND | ND |
| S147Gd | 41 ± 5 (1.3) | 12 ± 5 (11) | 23 ± 6 (4.0) | ND | ND |
| T66I/Q146P | 22 ± 2 (0.7) | 131 ± 12 (119) | 18 ± 5 (3.1) | ND | ND |
| T66I/Q146P/S147G | 19 ± 5 (0.6) | 453 ± 62 (412) | 127 ± 37 (22) | ND | ND |
| T66I/Q95K/Q146P/S147G | 31 ± 12 (1.0) | >1,000 | 303 ± 76 (52) | ND | ND |
| T66I/Q95K/E138K/Q146P/S147G | 41 ± 7 (1.3) | >1,000 | 306 ± 76 (53) | >10,000 | >50,000 |
| EVG mutation (expt 2)b | |||||
| H51Y | 34 ± 8 (1.1) | 4.0 ± 0.6 (3.6) | 3.3 ± 0.7 (0.6) | ND | ND |
| E92Q | 32 ± 4 (1.0) | 40 ± 12 (36) | 63 ± 39 (11) | ND | ND |
| E157Q | 34 ± 8 (1.1) | 6.9 ± 1.4 (6.3) | 52 ± 20 (9.0) | ND | ND |
| E92Q/S147G | 39 ± 9 (1.2) | 392 ± 133 (356) | 587 ± 64 (101) | ND | ND |
| H51Y/E92Q/S147G | 54 ± 6 (1.7) | 769 ± 88 (699) | 374 ± 100 (64) | >10,000 | 22,175 ± 1,299 (30) |
| H51Y/E92Q/S147G/E157Q | 21 ± 2 (0.7) | >1,000 | 340 ± 26 (59) | >10,000 | 18,652 ± 4,575 (25) |
| L-870,810 mutation | |||||
| V72I | 17 ± 1 (0.5) | 4.3 ± 1.1 (3.9) | 9.1 ± 2.5 (1.6) | ND | ND |
| L74Mc | 20 ± 3 (0.6) | 3.3 ± 1.1 (3.0) | 4.4 ± 1.7 (0.8) | 1,500 ± 302 (1.2) | 4,471 ± 942 (6.1) |
| F121Y | 15 ± 1 (0.5) | 28 ± 11 (25) | 51 ± 23 (8.8) | ND | ND |
| T125K | 17 ± 3 (0.5) | 2.3 ± 1.1 (2.1) | 9.9 ± 3.7 (1.7) | ND | ND |
| V151I | 21 ± 4 (0.7) | 11 ± 3 (10) | 104 ± 29 (18) | ND | ND |
| G163R | 22 ± 7 (0.7) | 0.8 ± 0.2 (0.7) | 6.5 ± 2.6 (1.1) | ND | ND |
| F121Y/G163R | 36 ± 5 (1.1) | 60 ± 20 (55) | 219 ± 20 (38) | ND | ND |
| F121Y/T125K | 38 ± 12 (1.2) | 195 ± 73 (177) | 393 ± 82 (68) | ND | ND |
| V72I/F121Y/T125K | 33 ± 7 (1.0) | 143 ± 25 (130) | 886 ± 79 (153) | ND | ND |
| V72I/F121Y/T125K/V151I | 64 ± 9 (2.0) | >1,000 | >1,000 | >10,000 | >50,000 |
| DKA mutation | |||||
| T66I/L74M | 46 ± 11 (1.4) | 49 ± 5 (45) | 41 ± 10 (7.1) | >10,000 | 23,043 ± 4,886 (31) |
| T66I/S153Y | 26 ± 8 (0.8) | 285 ± 63 (259) | 29 ± 9 (5.0) | >10,000 | 8,478 ± 1,267 (12) |
a
Antiviral activity was determined using the MAGI assay. Data shown are means and standard deviations obtained from at least three independent experiments, and resistance (n-fold) of the EC50 of the IN recombinant molecular clone compared to that of parental HIV-1WT is shown in parentheses. ND, not determined.
b
EVG selection was performed in two independent experiments, and observed mutations are separately represented.
c
Also observed in the DKA selected mutation.
d
Observed in two independent EVG-selected experiments.