Abstract
Detailed clonal phenotypic/genotypic analyses explored viral-escape mechanisms during maraviroc-based therapy in highly treatment-experienced participants from the MOTIVATE trials. To allow real-time assessment of samples while maintaining a blind trial, the first 267 enrolled participants were selected for evaluation. At failure, plasma samples from 20/50 participants (16/20 maraviroc-treated) with CXCR4-using virus and all 38 (13 maraviroc-treated) with CCR5-tropic virus were evaluated. Of those maraviroc-treated participants with CXCR4-using virus at failure, genotypic and phenotypic clonal tropism determinations showed >90% correspondence in 14/16 at Day 1 and 14/16 at failure. Phylogenetic analysis of clonal sequences detected pre-treatment progenitor CXCR4-using virus, or on-treatment virus highly divergent from the Day 1 R5 virus, excluding possible co-receptor switch through maraviroc-mediated evolution. Re-analysis of pre-treatment samples using the enhanced-sensitivity Trofile® assay detected CXCR4-using virus pre-treatment in 16/20 participants failing with CXCR4-using virus. Post-maraviroc reversion of CXCR4-use to CCR5-tropic occurred in 7/8 participants with follow-up, suggesting selective maraviroc inhibition of CCR5-tropic variants in a mixed-tropic viral population, not emergence of de novo mutations in CCR5-tropic virus, as the main virologic escape mechanism. Maraviroc-resistant CCR5-tropic virus was observed in plasma from 5 treated participants with virus displaying reduced maximal percent inhibition (MPI) but no evidence of IC50 change. Env clones with reduced MPI showed 1–5 amino acid changes specific to each V3-loop region of env relative to Day 1. However, transferring on-treatment resistance-associated changes using site-directed mutagenesis did not always establish resistance in Day 1 virus, and key ‘signature’ mutation patterns associated with reduced susceptibility to maraviroc were not identified. Evolutionary divergence of the CXCR4-using viruses is confirmed, emphasizing natural selection not influenced directly by maraviroc; maraviroc simply unmasks pre-existing lineages by inhibiting the R5 virus. For R5-viral failure, resistance development through drug selection pressure was uncommon and manifested through reduced MPI and with virus strain–specific mutational patterns.
Highlights
HIV-1 entry into cells requires initial virus-cell contact via the CD4 receptor followed by coreceptor binding, most commonly through CCR5 (R5) [1]
The first 267 participants enrolled in the MOTIVATE 1 and 2 clinical studies were included in this study, and the analysis was performed after the last participant had reached Week 24 and while the study was still fully blinded (S1 Fig)
The exploratory analysis of mechanisms associated with virologic failure in the MOTIVATE 1 and 2 studies was carried out on a subset of the first 267 participants to be enrolled in the studies
Summary
HIV-1 entry into cells requires initial virus-cell contact via the CD4 receptor followed by coreceptor binding, most commonly through CCR5 (R5) [1]. CXCR4 provides an alternative coreceptor, with increased prevalence of CXCR4-using virus in later stages of disease in approximately 50% of infected individuals [2]. Dual-tropic or mixedtropism (DM) viral populations can use both the CCR5 and CXCR4 co-receptors (dual tropic) or comprise a mixed tropism population, where viruses use either co-receptor and are co-existing [4,5]. As dual- or mixed-tropic viruses cannot be distinguished readily in phenotypic or genotypic assays, they are referred to as infections with DM tropism; clonal analyses can distinguish true dual-tropic virus from CXCR4-tropic (X4) virus. Tropism can be predicted using the amino acid sequence of the 3rd variable loop of env (V3-loop) and viruses classified as R5 or non-R5 [6,7,8,9]
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