Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance

• DOI: 10.1073/pnas.1010246107
• Publication Date: 2010-10-29T04:29:34Z
• Authors: Stephen Hare; Ann M. Vos; Reginald F. Clayton; Jan W. Thuring; Maxwell D. Cummings; Peter Cherepanov
• Keywords: Raltegravir; Elvitegravir; Cocrystal; Integrase inhibitor; Integrases

The development of HIV integrase (IN) strand transfer inhibitors (INSTIs) and our understanding viral resistance to these molecules have been hampered by a paucity available structural data. We recently reported cocrystal structures the prototype foamy virus (PFV) intasome with raltegravir elvitegravir, establishing general INSTI binding mode. now present an expanded set containing PFV intasomes complexed first- second-generation INSTIs at resolutions up 2.5 Å. Importantly, improved resolution allowed us refine complete coordination spheres catalytic metal cations within INSTI-bound active site. show that like Q148H/G140S N155H HIV-1 IN variants, analogous S217H N224H INs display reduced sensitivity in vitro. Crystal mutant INSTI-free -bound forms revealed amino acid substitutions necessitate considerable conformational rearrangements site accommodate INSTI, thus explaining their adverse effects on antiviral activity. Furthermore, predict physical proximity interaction between residues His148 Ser/Ala140, rationalizing coevolution Q148H G140S/A mutations drug-resistant strains.