Implications of HIV-1 M group polymorphisms on integrase inhibitor efficacy and resistance: genetic and structural in silico analyses.
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.
Loizidou
Eriketi Z
EZ
Department of Biology, University of Cyprus, 75 Kallipoleos Avenue, P.O. Box 20537, 1678 Nicosia, Cyprus.
Kousiappa
Ioanna
I
Zeinalipour-Yazdi
Constantinos D
CD
Van de Vijver
David A M C
DA
Kostrikis
Leondios G
LG
D001665:Binding Sites; D024882:Drug Resistance, Viral; D019427:HIV Integrase / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D009154:Mutation; D011110:Polymorphism, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D011760:Pyrrolidinones / Q000737:chemistry* / Q000494:pharmacology; D000068898:Raltegravir Potassium
D019428:HIV Integrase Inhibitors; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1