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

• Published in: PloS one 2018-12, Vol.13 (12), p.e0204099
• Main Authors: Lewis, Marilyn, Mori, Julie, Toma, Jonathan, Mosley, Mike, Huang, Wei, Simpson, Paul, Mansfield, Roy, Craig, Charles, van der Ryst, Elna, Robertson, David L, Whitcomb, Jeannette M, Westby, Mike
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Amino acid sequence; Amino acids; Antiretroviral drugs; Biology and Life Sciences; Care and treatment; CCR5 protein; Computer and Information Sciences; CXCR4 protein; Development and progression; Disease resistance; Divergence; Failure analysis; Female; Gene mutation; Genetic aspects; Genotype; Genotypes; Health aspects; HIV; HIV infections; HIV Infections - drug therapy; HIV Infections - genetics; HIV Infections - pathology; HIV-1 - genetics; Human immunodeficiency virus; Humans; Inhibition; Male; Maraviroc - administration & dosage; Maraviroc - adverse effects; Medicine and Health Sciences; Middle Aged; Mutation; Natural selection; Phylogeny; Research and Analysis Methods; Reversion; Sensitivity analysis; Sensitivity enhancement; Site-directed mutagenesis; Treatment Failure; Treatment resistance; Tropism; Viral Tropism - drug effects; Viral Tropism - genetics; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0204099

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.