V1 and V2 domains of HIV envelope contribute to CCR5 antagonist resistance
Abstract
Vicriviroc (VCV) is a CCR5 antagonist that blocks the viral entry of CCR5-tropic (R5) virions by binding to and inducing a conformational change in the chemokine receptor. Clinical resistance to CCR5 antagonists occurs in two phases, competitive and noncompetitive stages. In this study, we analyzed two subjects, from a phase 2b VCV clinical trial, whose quasispecies contained R5 and dual-mixed virions at the earliest recorded time of virological failure (VF). Genotypic analysis of R5-tropic patient-derived envelope genes revealed significant changes in the V1/V2 coding domain and convergence toward a more homogenous sequence under VCV therapy. Additionally, a small population of baseline clones sharing similar V1/V2 and V3 domains with the predominant VF isolate was observed. These clones were denoted preresistant based on their genotype. Preresistant clones and chimeric clones containing V1/V2 regions isolated during VF displayed high 50% inhibitory concentration (IC
