In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject

Abstract

Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs.

FIG. 1.

VCV susceptibility of HIV-1 from a subject for whom VCV-containing antiretroviral therapy failed. VCV susceptibility was examined at week 0 (study entry) (a), week 2 (b), week 8 (c), week 19 (d), week 24 (e), week 28 (f), and week 48 (20 weeks after VCV discontinuation) (g) by using the PhenoSense entry assay (Monogram Biosciences, South San Francisco, CA) (21). Susceptibilities were plotted as micromolar drug concentrations versus the percent viral inhibition relative to the infection level in the absence of the drug. The vertical dashed lines indicate the 50% inhibitory concentration for VCV.

FIG. 2.

Alignment of V3 loop sequences from independent clones obtained at weeks 0, 16, 19, 28, and 48. The predominant clone at baseline (week 0) was designated the reference clone. Predicted amino acid differences are shown, and similarities are indicated with dashes. The number of independent clones with the same sequence is indicated to the left of each sequence. VF, virologic failure.

FIG. 3.

VCV susceptibilities of recombinant viruses with full-length and chimeric envelopes. In each graph, the percentages of inhibition relative to the viral level in the no-drug control at various inhibitor concentrations are shown. (a) VCV susceptibilities of recombinant viruses with the predominant full-length envelope at sequential time points after VCV initiation. (b) Schematic representation of the chimeric envelopes; amino acid numbering is based on the HxB2 reference sequence. (c) VCV susceptibility of recombinant virus expressing a chimeric envelope with week 28 gp41 substituting within the week 0 envelope. (d) VCV susceptibilities of recombinant viruses expressing chimeric envelopes with week 28 envelope segments substituting for week 0 envelope regions. Error bars represent the standard errors of the means of results from two to four experiments, each performed in triplicate. Nonlinear regression was used to estimate a fitted curve.

FIG. 4.

Resistance to VCV modulates sensitivities to other entry inhibitors. In each graph, percentages of inhibition relative to the viral level in the no-drug control at various TAK779 (a), HGS004 (b), AOP-RANTES (c), and ENF (d) concentrations are shown. Error bars represent the standard errors of the means of results from two to four experiments, each performed in triplicate. Nonlinear regression was used to estimate a fitted curve.