Implications of HIV-1 M group polymorphisms on integrase inhibitor efficacy and resistance: genetic and structural in silico analyses

Biochemistry. 2009 Jan 13;48(1):4-6. doi: 10.1021/bi8019349.

Abstract

The extensive polymorphisms among HIV-1 subtypes have been implicated in drug resistance development. Integrase inhibitors represent the latest addition to the treatment of HIV-1, and their efficacy and resistance patterns among M group strains are currently under investigation. This study analyzed the intersubtype variation within 108 integrase sequences from seven subtypes. The residues associated with catalytic activity and primary resistance to raltegravir were highly conserved among all strains. Variations were observed in residues associated with secondary resistance. Molecular modeling studies indicated a two-way binding mode of raltegravir that explains the resistance pathways and the implication of nonconservative mutations in integrase-raltegravir interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Drug Resistance, Viral*
  • HIV Integrase / genetics*
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / pharmacology
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Models, Molecular
  • Mutation
  • Polymorphism, Genetic
  • Protein Binding
  • Protein Conformation
  • Pyrrolidinones / chemistry*
  • Pyrrolidinones / pharmacology
  • Raltegravir Potassium

Substances

  • HIV Integrase Inhibitors
  • Pyrrolidinones
  • Raltegravir Potassium
  • HIV Integrase
  • p31 integrase protein, Human immunodeficiency virus 1