Fig 1.
Protease processed HIV-1 Gag polyprotein and amino acid differences that contribute to reduced bevirimat (BVM) susceptibility.
(Top): Gag region from HIV-1 showing segments of the structural proteins cleaved by HIV Pr. Bottom: Blowup of region surrounding SP1; amino acids observed as substitutions resulting in reduced susceptibility to BVM in vitro are shown in the red box. Polymorphic amino acid variations within and near SP1 that reduce BVM susceptibility are shown in the grey box. Figure adapted from [12].
Table 1.
Genotypic and phenotypic changes selected by serial passage of wild-type virus with GSK3532795.
Table 2.
Genotypic and phenotypic changes selected by serial passage of V370A virus with GSK3532795.
Table 3.
Amino acid substitutions selected in Gag during passage at a high fixed concentration of GSK3532795 (30xEC50).
Table 4.
Antiviral sensitivities of site-directed mutants.
Fig 2.
Baseline GSK3532795 susceptibility relative to number of Gag polymorphisms in plasma-derived virus from patients included in part A of the phase 2a study (AI468002).
Baseline PMs included any change at V362, A364, Q369, V370, or T371. Black lines show the median for each group. FC-EC50, fold-change in 50% effective concentration relative to reference virus; PM = polymorphism.
Fig 3.
Maximum viral load decline during 10-day monotherapy with GSK3532795 according to dose and detection of HIV-1.
Baseline polymorphisms included any change at V362, A364, Q369, or V370, unless otherwise indicated. Open circle: single polymorphism; closed circle: ≥2 polymorphisms; line: mean value of log10 HIV RNA.
Table 5.
Baseline and day 10 on-treatment genotype and phenotype in the AI468002a.
Fig 4.
Model of the CA-SP1/GSK3532795 complex.
The protein is depicted in a white and yellow semi-transparent cartoon representation with the locations of residues 286, 326, 332, 333, 362, 364, and 370 highlighted with pink, blue, cyan, purple, red, magenta, and orange spheres, respectively. GSK3532795 is shown in ball and stick representation with green carbon atoms. Image created with PyMol (2.1.1, Schrödinger, LLC).
Fig 5.
Protein environments of A364 (A, top) and V362 (B, bottom) in the CA-SP1/GSK3532795 complex model. The protein backbone is depicted in white and yellow cartoon representation with helix 10 and the 352–356 β-turn colored blue and red, respectively. GSK3532795 and specific residues are shown in ball and stick style with carbon atoms colored magenta (A364, V362), green (GSK3532795), or orange. Image created with PyMol (2.1.1, Schrödinger, LLC).