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.

Cabotegravir（CAB，S / GSK1265744）是研究性的第二代整合酶链转移抑制剂（INSTI），化学结构类似于dolutegravir。CAB正在开发作为一种长效可注射制剂，用于治疗HIV-1感染和预防接触前。我们进行了在体外在CAB的存在raltegravir-或埃替拉韦抗性签名突变体的通道的研究来表征这种药物的电阻分布。在Q148H病毒传播期间，G140S在第14天出现，随后是G149A和C56S。使用定点诱变，我们获得了在整合酶编码区中包含编码C56S和G149A突变的HIV分子克隆。这些取代在体外得到了表征作为与INSTI耐药相关的次级耐药突变。加入了C56S和G149A的标志性突变病毒G140S / Q148H在整合活性降低的情况下获得了更高的INSTI抵抗力，这导致在无药条件下生长变慢。