Background: 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. S-1360 and 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 IC95’s of 12000 and 100 nM, respectively. Although structurally distinct, the compounds have identical mechanisms of action and compete for binding to the same site.

Methods: 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 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.

Results: All of the inhibitors evaluated selected for similar but not identical mutations in integrase. Although in each case the mutations were localized to the integrase active site proximal to the residues that coordinate the catalytic metal ions, marked differences were observed in the susceptibility profiles both within and between each class of integrase inhibitors. Some compounds including S-1360 were significantly affected by a wide variety 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 which were effective against all of the resistant variants tested.  

Conclusions: Despite the apparent structural differences, there appears to be a significant potential for cross resistance between S-1360 and L-870810, the two integrase inhibitors currently in clinical development. However, these studies suggest it may be possible to identify novel integrase inhibitors with distinct resistance profiles and thus develop a therapy sequencing strategy for future agents within this new class.