HIV-1 Coreceptor Usage Assessment by Ultra-Deep Pyrosequencing and Response to Maraviroc

PLoS One. 2015 Jun 11;10(6):e0127816. doi: 10.1371/journal.pone.0127816. eCollection 2015.

Abstract

Background: Maraviroc is an HIV entry inhibitor that alters the conformation of CCR5 and is poorly efficient in patients infected by viruses that use CXCR4 as an entry coreceptor. The goal of this study was to assess the capacity of ultra-deep pyrosequencing (UDPS) and different data analysis approaches to characterize HIV tropism at baseline and predict the therapeutic outcome on maraviroc treatment.

Methods: 113 patients with detectable HIV-1 RNA on HAART were treated with maraviroc. The virological response was assessed at months 1, 3 and 6. The sequence of the HIV V3 loop was determined at baseline and prediction of maraviroc response by different software and interpretation algorithms was analyzed.

Results: UDPS followed by analysis with the Pyrotrop software or geno2pheno algorithm provided better prediction of the response to maraviroc than Sanger sequencing. We also found that the H34Y/S substitution in the V3 loop was the strongest individual predictor of maraviroc response, stronger than substitutions at positions 11 or 25 classically used in interpretation algorithms.

Conclusions: UDPS is a powerful tool that can be used with confidence to predict maraviroc response in HIV-1-infected patients. Improvement of the predictive value of interpretation algorithms is possible and our results suggest that adding the H34S/Y substitution would substantially improve the performance of the 11/25/charge rule.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Algorithms
  • Antiretroviral Therapy, Highly Active
  • Area Under Curve
  • Cyclohexanes / therapeutic use*
  • Female
  • HIV Envelope Protein gp120 / chemistry
  • HIV Infections / drug therapy*
  • HIV-1 / physiology*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Maraviroc
  • Middle Aged
  • Peptide Fragments / chemistry
  • RNA, Viral / analysis
  • ROC Curve
  • Sequence Analysis, RNA
  • Software
  • Triazoles / therapeutic use*
  • Viral Tropism

Substances

  • Cyclohexanes
  • HIV Envelope Protein gp120
  • HIV envelope protein gp120 (305-321)
  • Peptide Fragments
  • RNA, Viral
  • Triazoles
  • Maraviroc

Grants and funding

This research has been funded as part of the project “Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)“ within the 7th Framework Program of the European Community (FP7) and by the National Agency for Research on AIDS and Viral Hepatitis (ANRS). C.R. is the recipient of a pre-doctoral fellowship from ANRS.