Resistance to HIV-1 integrase inhibitors: A structural perspective.
Strand-transfer inhibitors, of which raltegravir, elvitegravir and S/GSK1349572, is a new class of antiretrovirals that inhibit HIV integrase-catalyzed insertion of the HIV-1 genome into cell chromosomes. The results of clinical trials were very encouraging regarding their viral efficiency and tolerance. However resistance mutations were identified in patients failing to respond to treatment with these inhibitors, involving primary mutations as well as numerous secondary mutations. This review focuses on recent advanced computational studies that have highlighted the contribution of those residues subject to primary mutations and the role of conformational flexibility of the enzyme in binding to strand-transfer inhibitors.
Mouscadet
Jean-François
JF
LBPA, CNRS, Ecole Normale Supérieure de Cachan, Cachan cedex, France. mouscadet@lbpa.ens-cachan.fr
Delelis
Olivier
O
Marcelin
Anne-Geneviève
AG
Tchertanov
Luba
L
D004279:DNA, Viral / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D055503:Protein Multimerization
D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1