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Cabotegravir (CAB, S/GSK1265744) is an investigational second-generation integrase strand transfer inhibitor (INSTI) with a chemical structure similar to dolutegravir. CAB is under development as a long-acting injectable formulation for treatment of HIV-1 infection and for pre-exposure prophylaxis. We conducted an in vitro passage study of raltegravir- or elvitegravir-resistant signature mutants in the presence of CAB to characterize the resistance profile of this drug. During passage with Q148H virus, G140S arose by day 14, followed by G149A and C56S. Using site-directed mutagenesis, we obtained HIV molecular clones containing mutations encoding C56S and G149A in the integrase-coding region. Those substitutions were characterized in vitro as INSTI-resistance-associated secondary resistance mutations. Signature mutant viruses G140S/Q148H in which C56S and G149A were added acquired further INSTI resistance in conjunction with diminished integration activity, which yielded slower growth under drug-free conditions.G149A and C56S were identified as novel integrase strand transfer inhibitor resistance secondary mutations in vitro.G149A was a resistant responsible mutation to CAB and other INSTIs.C56S was a responsible mutation for recovering fitness.