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12th International HIV Drug Resistance Workshop10–14 June 2003, Cabo del Sol, Los Cabos, Mexico |
Inhibitors of the integrase strand transfer reaction have been shown to be effective inhibitors of integration and HIV-1 replication in vitro and in vivo. The diketone S-1360 and the napthyridine L-870810 are the first compounds in this novel class to enter into clinical studies in HIV-1-infected patients. In the presence of human serum, S-1360 and L-870810 inhibit HIV-1 replication in cell culture with IC95s of 12000 and 100 nM, respectively. Although structurally distinct, the compounds have identical mechanisms of action and compete for binding to the same site. In an attempt to understand the potential for cross resistance within this new class of agents we have used a variety of diketones and naphthyridines related to S-1360 and L- 870810, respectively, to select resistant HIV-1 variants in vitro. Mutations in integrase were identified upon sequencing each of the resistant virus populations. The observed mutations were introduced into an isogenic virus background and the recombinant viruses were then used to evaluate their respective susceptibility to a panel of integrase inhibitors from each structural class. All of the inhibitors we evaluated selected for similar but not identical mutations in integrase. In each case the mutations were localized to the integrase active site proximal to the residues that coordinate the catalytic metal ions (D64, D116 and E152). Although similar mutations were selected with a variety of structurally diverse compounds, marked differences were observed in the susceptibility profiles of these inhibitors both within and between each structural class. Some compounds including S-1360 were affected by a wide range of different mutations, while other inhibitors, including L-870810, displayed an overlapping but more restricted resistance profile. In the course of this extensive evaluation we also identified compounds that exhibited apparently discrete resistance profiles and integrase inhibitors that were effective against all of the resistant variants we have identified to date. These analyses demonstrate it is possible to identify integrase inhibitors with distinct resistance profiles, however there appears to be a significant potential for cross resistance between many such compounds (such as, S-1360 and L-870810) despite their apparent differences in structure. Localization of the critical determinants for resistance to the integrase active site is consistent with biochemical studies that demonstrate these inhibitors function by sequestering the active site metals in integrase and the observation that similar compounds have been identified which inhibit mechanistically- related metal-dependent phosphotransferases such as HIV-1 RNase H.
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2003-07-08
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