Clonal analysis of HIV-1 genotype and function associated with virologic failure in treatment-experienced persons receiving maraviroc: Results from the MOTIVATE phase 3 randomized, placebo-controlled trials

Lewis, M. et al. (2018) Clonal analysis of HIV-1 genotype and function associated with virologic failure in treatment-experienced persons receiving maraviroc: Results from the MOTIVATE phase 3 randomized, placebo-controlled trials. PLoS ONE, 13(12), e0204099. (doi: 10.1371/journal.pone.0204099) (PMID:30586365) (PMCID:PMC6306210)

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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.

Item Type:Articles
Additional Information:This work was funded by Pfizer Inc. and ViiV Healthcare. Pfizer Inc. provided support in the form of salaries for authors ML, JM, MM, PS, RM, CC, EV, and MW, and latterly consultancy fees for authors ML, CC, and EV through The Research Network Ltd. Monogram Biosciences received a fee for service from Pfizer and they provided support in the form of salaries for authors JT, WH, and JMW. DLR received a grant from the Medical Research Council (MRC) and consultancy fees from Pfizer. JT reports a grant from Small Business Innovation Research (Grant number: 1 R21 AI114399) outside of the of the submitted work, and a fee for service from Pfizer during the conduct of the study. The specific roles of all these authors are articulated in the ‘author contributions’ section. The funders had a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript through the provision of expert decision-making input from clinical and management teams.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Robertson, Professor David
Authors: Lewis, M., Mori, J., Toma, J., Mosley, M., Huang, W., Simpson, P., Mansfield, R., Craig, C., van der Ryst, E., Robertson, D. L., Whitcomb, J. M., and Westby, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN:1932-6203
ISSN (Online):1932-6203

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
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