TABLE 2.
Antiviral activity of vicriviroc against HIV-1 pseudotyped viruses resistant to enfuvirtide, reverse transcriptase, and protease inhibitors
| Virus tested | Phenotypea | Amino acid (aa) changes relative to WT
|
EC50b (nM) | Fold change in IC50c | ||
|---|---|---|---|---|---|---|
| Reverse transcriptase (aa 1-305) | Protease (aa 1-99) | gp41 (aa 1-397) | ||||
| 1 | WT | WT | WT | WT | 18.3 | 1.00 |
| 2 | Enfuvirtide resistant | WT | WT | V38A | 8.7 | 0.48 |
| 3 | Enfuvirtide resistant | WT | WT | G36D, V38M | 32.9 | 1.8 |
| 4 | PR-RT MDR | V35V/I, T39E, M41L, E44D, D67N, K70R, L74I, K101P, Q102K, K103S, V118I, K122E, I135L, D177N, M184V, T200A, E203E/D/K/N, L210W, R211K, T215Y, D218E, K219E, L228H, R277K | L10I, T12P/S, I13V, L19P, K20M, L33I, E35D, M36I, N37D, M46M/I, G48V, I54T, I62I/V, L63P, I64V, T74S, V82A, N83N/S, T91T/S, I93I/M | WT | 14.1 | 0.77 |
| 5 | PR-RT MDR | P4S, V35L, M41L, E44D, D67N, K70R, L74I, V75S, K101E/Q, Q102K, L109I, V118I, K122E, I135V, C162S, V179F, Y181C, G190A, G196E, L210W, R211K, T215Y, D218E, K219E, L228H, Q242H, S251I, A272S, R277K, L283I, A288T | L10I, L33F, K43T, G48V, I50V, I54V, I62V, L63P, I64V, I72I/M, G73V, V77I, V82A, L90L/M | WT | 12.3 | 0.67 |
| 6 | RTI resistant | E6K, K20R, V35M, M41L, K43E, E44A, D67N, T69D, Q102K, V106I, T107S, L109I, V118I, K122E, I135T, R172K, K173N, Q174K, I178L, Y181C, M184V, Y188L, E203A, H208Y, L210W, R211K, T215Y, D218E, K219N, H221Y, L228H, R277K, T286A, V293I, E297K | L10L/I, V11V/I, L63P | WT | 23.4 | 1.28 |
| 7 | PI resistant | V35I, T39A, Q102K, V111I, K122E, C162S, F214L, S251I, R277K, V293I | L10F, L19L/I, K20M/R, L23L/I, E35E/D, M36I, R41R/K, M46L, I54V, I62I/V, L63P, A71V, V82A, I84I/V, L90M, I93L | WT | 28.1 | 1.53 |
WT, wild type; PR, protease; RT; reverse transcriptase; MDR, multidrug resistant; RTI, RT inhibitor; PI, protease inhibitor.
Vicriviroc sensitivity against viral pools harboring the indicated mutations in the RT, PR, or gp41 genes, relative to the WT control virus, was determined using the PhenoSense assay (16). EC50s were derived from a 9-point dose-response curve (concentration range, 0.01 to 667 nM; n = 2 wells/concentration) and are defined as the concentration of vicroviroc required to inhibit the mean luciferase signal by 50% relative to untreated control wells.
Fold change in EC50 relative to the HIV pseudovirus generated with WT RT-PR and parental JrCSF envelope sequences.