TABLE 7.
Activities of the BDM-2 series against HIV-1 strains resistant to drugs currently used in clinica
| Drug class | Compound | Fold change in EC50 in multiple-round infection assays relative to NL4-3 |
|||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| INSTIs |
NRTI/NNRTIs |
PIs |
|||||||||||||||||
| E92Q | Y143R | N155H | T97A/N155H (pat.) | G140S | Q148H | G140S/Q148H | G140S/Q148H (pat.) | E92Q/N155H (pat.) | NLAY351717 | NLAY351753 | K103N/Y181C | ARP-4595 | ARP-4596 | ARP-11801 | ARP-11803 | ARP-11807 | ARP-11808 | ||
| INLAI | BDM-2 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 0.5 | 1 | 1 | 1 | 1 |
| MUT871 | 1 | 1 | 1 | NT | 1 | 1 | 1 | NT | NT | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | |
| MUT872 | 1 | 0.5 | 1 | NT | 1 | 1 | 1 | NT | NT | 1 | 1 | 1 | 1 | 1 | 2 | 1 | 1 | 2 | |
| MUT884 | 1 | 0.5 | 1 | NT | 1 | 1 | 1 | NT | NT | 1 | 1 | 1 | 1 | 1 | 3 | 2 | 1 | 2 | |
| MUT916 | 1 | 0.4 | 1 | NT | 1 | 1 | 1 | NT | NT | 1 | 2 | 1 | 2 | 1 | 2 | 2 | 2 | 2 | |
| BI-224436 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0.4 | 0.5 | 1 | 1 | 1 | 1 | |
| S-I-82 | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | NT | 1 | 0.5 | 1 | 1 | 1 | 1 | |
| INSTI | RAL | 3 | 14 | 6 | 140 | 1 | 9 | 190 | 440 | 31 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 2 | 2 |
| EVG | 24 | 2 | 12 | 440 | 2 | 3 | 2500 | 2000 | 200 | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 2 | 2 | |
| DTG | NT | 0.4 | 0.3 | 3 | 0.6 | 0.3 | 2 | 3 | 1 | 0.4 | 1 | 0.3 | 1 | 0.5 | 1 | 1 | 2 | 1 | |
| NRTI | AZT | 1 | 1 | 1 | 4 | 1 | 1 | 1 | 1 | 1 | 150 | 210 | 0.1 | 2 | 1 | 1 | 2 | 2 | 5 |
| NNRTI | EFV | 1 | 1 | 1 | 2 | 1 | 1 | 1 | 1 | 1 | 2 | 39 | 51 | 1 | 1 | 0.5 | 1 | 2 | 1 |
| RPV | NT | NT | NT | 1 | 1 | 1 | 1 | 1 | 1 | 1 | 0.4 | 3 | 1 | 1 | 0.4 | 1 | 1 | 1 | |
| PI | IDV | 1 | 1 | 1 | NT | NT | NT | 1 | NT | NT | 1 | 1 | 1 | 5 | 8 | 92 | 260 | 36 | 59 |
| DRV | NT | NT | NT | NT | NT | NT | 1 | NT | NT | 1 | 1 | 1 | 1 | 1 | 31 | 24 | 12 | 240 | |
Activities of INLAIs and clinical antiretrovirals against HIV-1 strains resistant to INSTIs, nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), or protease inhibitors (Pis). HIV-1 strains are indicated by their respective resistance mutations (in the NL4-3 background) or by specific clone names. The NRTI and NRTI/NNRTI inhibitor-resistant clones NLAY351717 and NLAY351753 contained RT coding regions from GenBank sequence identifiers AY351717 and AY351753, respectively. The representative PI-resistant viruses ARP-4595 (harboring mutations M46I/L63P/V82T/I84V in the protease coding region), ARP-4596 (L10R/M46I/L63P/V82T/I84V), ARP-11801 (L10F/G16A/L33F/K43T/L63P/A71V/V82A), ARP-11803 (L33F/E34T/K43T/G48V/I54S/L63P/A71V/V82A), ARP-11807 (L33F/I47A/L63P/A71V/V82A), and ARP-11808 (L10F/T12P/L19P/K20T/L33F/E35G/L63P/K70T/A71V/G73S/P79A) were obtained from the NIH AIDS Reagent Program. Pat. Indicates primary patient-derived strain. Antiviral activities reported as EC50 fold change compared to wild type NL4-3 HIV-1 strain. Fold-change values >5 and >50 highlighted in light and dark gray, respectively. The reference compounds included examples of each drug class as well as two other INLAIs (BI-224436, S-I-82). EFV, efavirenz; RPV, rilpivirine; IDV, indinavir; DRV, darunavir. NT, not tested.