Table 2.
Novel non-nucleoside RT inhibitor resistance associated mutations
| Site-directed Mutants a | LDA 3F b | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Mutation c | N wt d | N mut e | NVP | EFV | ETR | max(F1) | max(n 11 ) f | min(cutoff) h | |
| V179M | 67699 | 31 | 0.8-2.3 | 0.3-0.4 | 0.4-0.9 | 0.327 (EFV) | 13 (ETR) | 8/(8 + 10) (EFV) | 1.35 (ETR) |
| H221L | 76783 | 31 | 4.2-5.0 | 1.5-1.6 | 1.1 | 0.118 (EFV) | 2 (EFV) | 2/(2 + 1) (EFV) | 2.03 (ETR) |
| V179Y | 67699 | 17 | 0.2-0.5 | < 0.2-0.2 | < 0.1-0.2 | 0.063 (ETR) | 16 (ETR) | 16/(16 + 472) (ETR) | 1.44 (ETR) |
| K219H | 67913 | 129 | 1.3-2.2 | 1.0-1.8 | 1.1-1.8 | 0.047 (ETR) | 14 (ETR) | 14/(14 + 447) (ETR) | 1.45 (ETR) |
| K219D | 67913 | 161 | 1.4-3.8 | 1.3-2.2 | 0.4-2.0 | 0.044 (ETR) | 24 (ETR) | 24/(24 + 894) (ETR) | 1.22 (ETR) |
| V179N | 67699 | 15 | 1.2-1.9 | 0.9-1.2 | 0.6-0.8 | 0.039 (ETR) | 8 (ETR) | 8/(8 + 391) (ETR) | 1.50 (ETR) |
| T376S | 15617 | 7415 | 2.8-3.4 | 1.5-2.0 | 1.6-2.1 | 0.035 (EFV) | 135 (EFV) | 135/(135 + 145) (EFV) | 1.67 (ETR) |
| Y181S | 72643 | 3 | NA | NA | NA | 0.019 (ETR) | 3 (ETR) | 3/(3 + 310) (ETR) | 1.45 (ETR) |
| L100V | 77197 | 8 | 6.4 (1) | 9.0-18.3 (2) | 1.1-1.2 (2) | 0.017 (ETR) | 6 (ETR) | 6/(6 + 678) (ETR) | 1.63 (ETR) |
| Y181F | 72643 | 9 | 1.1-2.0 | 0.4-0.8 | 0.4-0.7 | 0.016 (ETR) | 4 (ETR) | 4/(4 + 503) (ETR) | 1.33 (ETR) |
| K102L | 72791 | 12 | 2.3-2.9 | 0.5-1.2 | 0.3-0.4 | 0.015 (ETR) | 4 (ETR) | 4/(4 + 505) (ETR) | 1.77 (ETR) |
| K101N | 72175 | 94 | 5.0 (1) | 2.8 (1) | 0.8 (1) | 0.015 (ETR) | 4 (ETR) | 4/(4 + 434) (ETR) | 1.66 (ETR) |
| V106L | 75529 | 44 | 0.5-0.6 | 0.7-1.1 | 0.2-0.3 | 0.015 (ETR) | 5 (ETR) | 5/(5 + 617) (ETR) | 1.69 (ETR) |
| E138A | 75869 | 1828 | 2.2-4.9 | 1.2-3.6 | 2.8-3.5 | 0.014 (ETR) | 14 (ETR) | 14/(14 + 157) (ETR) | 2.10 (ETR) |
| M357T | 44115 | 17866 | 0.9 (1) | 1.2 (1) | NA | 0.013 (ETR) | 117 (ETR) | 117/(117 + 199) (ETR) | 1.88 (ETR) |
| T139R | 76899 | 243 | 6.4-7.3 | 1.5-2.7 | 1.0-1.2 | 0.010 (ETR) | 2 (ETR) | 2/(2 + 137) (ETR) | 2.22 (ETR) |
| E370G | 75915 | 489 | NA | NA | NA | 0.007 (ETR) | 2 (ETR) | 1/(1 + 1) (EFV) | 2.38 (ETR) |
| I135T | 45829 | 18410 | NA | NA | NA | 0.006 (ETR) | 52 (ETR) | 52/(52 + 94) (ETR) | 2.16 (ETR) |
| L234I | 79037 | 98 | 0.6-1.0 | 1.6-2.3 | 0.9-1.1 | 0.004 (ETR) | 1 (ETR) | 1/(1 + 353) (ETR) | 1.95 (ETR) |
| S379C | 69973 | 3578 | NA | NA | NA | 0.001 (ETR) | 1 (ETR) | 1/(1 + 1) (ETR) | 3.35 (ETR) |
| R206I | 79051 | 8 | 1.0-1.7 | 0.4-0.7 | 0.5-0.9 | NA | 0 (ETR) | 0/(0 + 102) (ETR) | 2.33 (ETR) |
| S134N | 79041 | 19 | 1.2-2.1 | 0.6-0.7 | 0.8-0.9 | NA | 0 (ETR) | 0/(0 + 69) (ETR) | 2.45 (ETR) |
| H221C | 76783 | 59 | NA | NA | NA | NA | 0 (ETR) | 0/(0 + 20) (ETR) | 2.73 (ETR) |
| I382T | 78025 | 329 | 2.4-6.7 | 0.9-1.7 | 0.7-2.4 | NA | 0 (ETR) | 0/(0 + 2) (ETR) | 3.30 (ETR) |
| D237E | 78246 | 423 | NA | NA | NA | NA | 0 (EFV) | 0/(0 + 3) (EFV) | 3.67 (ETR) |
| N348T | 74372 | 170 | NA | NA | NA | NA | 0 (ETR) | 0/(0 + 0) (ETR) | 4.05 (ETR) |
| E399G | 66049 | 670 | NA | NA | NA | NA | 0 (ETR) | 0/(0 + 0) (ETR) | 4.10 (ETR) |
| G190T | 72912 | 10 | > 67.4 | 7.8-14.9 | 0.6-0.7 | NA | 0 (EFV) | 0/(0 + 2) (EFV) | 4.16 (ETR) |
| Y188F | 76892 | 41 | 1.4-1.9 | 0.3-0.5 | 0.2-0.6 | NA | 0 (NVP) | 0/(0 + 0) (NVP) | 4.70 (NVP) |
| L283I | 72462 | 5930 | NA | NA | NA | NA | 0 (ETR) | 0/(0 + 0) (ETR) | 5.01 (ETR) |
| K101A | 72175 | 50 | 8.8-13.4 | 4.1-5.6 | 1.5-1.8 | NA | 0 (EFV) | 0/(0 + 3) (EFV) | 5.04 (NVP) |
| K101D | 72175 | 7 | 13.3-18.9 | 5.7-6.8 | 1.0-1.3 | NA | 0 (EFV) | 0/(0 + 3) (EFV) | 5.08 (EFV) |
| T139K | 76899 | 348 | 4.4-5.8 | 1.2-2.3 | 2.4-3.0 | NA | 0 (ETR) | 0/(0 + 0) (ETR) | 5.10 (ETR) |
| T165L | 75078 | 183 | NA | NA | NA | NA | 0 (ETR) | 0/(0 + 0) (ETR) | 5.81 (ETR) |
| T386A | 59810 | 1756 | NA | 1.6 (1) | 0.5 (1) | NA | 0 (NVP) | 0/(0 + 0) (NVP) | 6.07 (NVP) |
| V241M | 78771 | 23 | 4.7-5.6 | 1.0-1.8 | 0.8-1.2 | NA | 0 (NVP) | 0/(0 + 0) (NVP) | 6.90 (NVP) |
| I382L | 78025 | 228 | NA | NA | NA | NA | 0 (NVP) | 0/(0 + 0) (NVP) | 7.30 (NVP) |
| G335S | 65035 | 1877 | NA | NA | NA | NA | 0 (ETR) | 0/(0 + 0) (ETR) | 7.55 (ETR) |
| E399D | 66049 | 10697 | NA | NA | NA | NA | 0 (ETR) | 0/(0 + 0) (ETR) | 7.98 (ETR) |
| R358K | 70517 | 5995 | NA | NA | NA | NA | 0 (NVP) | 0/(0 + 0) (NVP) | 8.06 (NVP) |
aFold-Change range from 3 measurements, unless otherwise indicated between brackets.
FC > Biological Cut-Off (BCO) in bold, FC ≤ BCO in italic; BCO for NVP is 6.0, BCO for EFV is 3.3 and BCO for ETR is 3.2.
bSummarized for the three non-nucleoside RT inhibitors (NNRTI).
cTop 40 mutations, ranked by max(LDA F1) descending, then by min(LDA cutoff) ascending. Mutations shown are from the list of 124 NNRTI mutations with RWF ≥ 0 and LDA cutoff > 0 for NVP, EFV and ETR. Known NNRTI positions or novel mutations listed in [32,33] are shown in bold.
dFrequency of wild-type (not within a mixture) in LDA data set.
eFrequency of mutation (not within a mixture) in LDA data set.
fn11 is the number of samples with amino acid mutation having a predicted phenotype above the LDA cutoff.
gn01 is the number of samples with wild type amino acid having a predicted phenotype above the LDA cutoff.
hCutoff in log Fold-Change (taking the wild-type and mutation frequency percentages as prior probabilities in the LDA can result in cutoff values outside of the range of the predicted phenotypes).