Background:  Our aim was to characterize the resistance properties of a new integrase inhibitor (INI) S/GSK364735, a 2-metal-binding naphthyridinone.

Methods:  Resistance mutations were identified by passaging HIV-1 IIIb in MT-2 cells, under increasing concentrations of S/GSK364735, followed by sequencing the integrase gene of passaged viruses. Phenotypic fold resistance of site-directed molecular clones was determined in HeLa-CD4 cells. Mutant virus fitness was assessed in single round infection assays using HeLa-CD4 cells.

Results:  Resistance to S/GSK364735 was first observed on day 42. The number of mutations increased as culture continued and the drug concentration increased. The overall composition of mutations were similar to those already reported for other INI, with Q148R and F121Y being the 2 main pathways observed for S/GSK364735. Comparison of fold resistance to S/GSK364735 with that of the other INI against a panel of INI resistant molecular clones showed significant cross resistance, although some specific mutations (e.g., P145S, T66I/E92Q) showed different effects. Viral fitness of selected single-mutation viruses (measured as relative infectivity to wild type) were:  0.02 (D64N/D116N), 0.1 (Q148K), 0.2 (Q148R), and 0.6 (E138K). Introduction of a secondary mutation, E138K, increased the reduced fitness of Q148R mutant virus and was consistent with the order of emergence of mutations during passage.

Conclusions:  Overall, S/GSK364735 had resistance properties (relative time to resistance and resistance profiles) similar to other reported INI. Increase in viral fitness due to addition of a secondary mutation was consistent with the reported clinical resistance of raltegravir (MK-0518) and elvitegravir (GS-9137) being driven primarily by double and not single mutations.