TABLE 4.

Antiviral activity of GRL-1388 and -1398 against laboratory darunavir-resistant HIV-1^a

Virus	Amino acid substitution(s) in protease	Mean EC50 in nM ± SD (fold change)
		DRV	GRL-1388	GRL-1398
cHIV-1ERS104pre	L63P	4.0 ± 1.0	2.5 ± 0.4	0.4 ± 0.1
HIV-1DRVRP10	L10I, I15V, K20R, L24I, V32I, M36I, M46L, I54V, I62V, L63P, K70Q, V82A, L88M	29.1 ± 0.9 (7)	24.6 ± 6.9 (10)	3.3 ± 0.3 (8)
HIV-1DRVRP20	L10I, I15V, K20R, L24I, V32I, M36I, M46L, L63P, A71T, V82A, L88M	214.1 ± 47.9 (54)	150.8 ± 46.7 (60)	21.9 ± 5.7 (54)

^aDRV-resistant HIV-1 variants were selected in vitro by propagating a mixture of eight _CLHIV-1_MDR isolates in the presence of increasing concentrations of DRV in MT-4 cells. Six of the eight isolates were the same as those used for drug susceptibility assay (Table 3). Amino acid substitutions identified in protease of the other two isolates compared to the consensus type B sequence cited from the Los Alamos database include L10I, I15V, E35D, N37E, K45R, I54V, L63P, A71V, V82T, L90M, I93L, and C95F in _CLHIV-1_MDR/A and L10R, N37D, M46I, I62V, L63P, A71V, G73S, V74I, V82T, L90M, and I93L in _CLHIV-1_MDR/SS. Numbers in parentheses represent the fold changes of EC₅₀s against each isolate compared to the EC₅₀s against HIV-1_ERS104pre. All assays were conducted in duplicate or triplicate, and the data shown represent mean values (±1 standard deviation) derived from the results of three independent experiments. PHA-PBMCs were derived from a single donor.