HIV-2 integrase polymorphisms and longitudinal genotypic analysis of HIV-2 infected patients failing a raltegravir-containing regimen

PLoS One. 2014 Mar 28;9(3):e92747. doi: 10.1371/journal.pone.0092747. eCollection 2014.

Abstract

To characterize the HIV-2 integrase gene polymorphisms and the pathways to resistance of HIV-2 patients failing a raltegravir-containing regimen, we studied 63 integrase strand transfer inhibitors (INSTI)-naïve patients, and 10 heavily pretreated patients exhibiting virological failure while receiving a salvage raltegravir-containing regimen. All patients were infected by HIV-2 group A. 61.4% of the integrase residues were conserved, including the catalytic motif residues. No INSTI-major resistance mutations were detected in the virus population from naïve patients, but two amino acids that are secondary resistance mutations to INSTIs in HIV-1 were observed. The 10 raltegravir-experienced patients exhibited resistance mutations via three main genetic pathways: N155H, Q148R, and eventually E92Q - T97A. The 155 pathway was preferentially used (7/10 patients). Other mutations associated to raltegravir resistance in HIV-1 were also observed in our HIV-2 population (V151I and D232N), along with several novel mutations previously unreported. Data retrieved from this study should help build a more robust HIV-2-specific algorithm for the genotypic interpretation of raltegravir resistance, and contribute to improve the clinical monitoring of HIV-2-infected patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drug Resistance, Viral / genetics*
  • Genotype
  • HIV Infections / drug therapy*
  • HIV Integrase / genetics*
  • HIV Integrase Inhibitors / therapeutic use
  • HIV-1 / drug effects
  • HIV-2 / drug effects*
  • HIV-2 / genetics*
  • Humans
  • Polymorphism, Genetic / genetics*
  • Pyrrolidinones / therapeutic use*
  • Raltegravir Potassium

Substances

  • HIV Integrase Inhibitors
  • Pyrrolidinones
  • Raltegravir Potassium
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 2

Grants and funding

This work was funded by a research grant from Merck & Co., Inc., Whitehouse Station, N.J., USA, and by the European Commission's Seventh Framework Programme (FP7/2007–2013) under the project “Collaborative HIV and Anti-HIV Drug Resistance Network” (CHAIN, grant 223131). J.C.-S. was supported by Fundação para a Ciência e Tecnologia (FCT) with a PhD grant no. SFRH/BD/61141/2009. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.