Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka, Japan.
Antiviral Res. 2018 Apr;152:1-9. doi: 10.1016/j.antiviral.2018.01.013. Epub 2018 Feb 1.
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.
卡博特韦（CAB，S/GSK1265744）是一种研究中的第二代整合酶链转移抑制剂（INSTI），其化学结构与度鲁特韦相似。CAB 正在开发作为长效注射制剂，用于治疗 HIV-1 感染和暴露前预防。我们在存在 CAB 的情况下对 raltegravir 或 elvitegravir 耐药的特征突变体进行了体外传代研究，以描述该药物的耐药谱。在 Q148H 病毒传代过程中，G140S 于第 14 天出现，随后是 G149A 和 C56S。通过定点突变，我们获得了含有编码整合酶编码区 C56S 和 G149A 突变的 HIV 分子克隆。这些取代在体外被表征为与 INSTI 耐药相关的次要耐药突变。添加了 C56S 和 G149A 的特征突变体病毒 G140S/Q148H 获得了进一步的 INSTI 耐药性，同时整合活性降低，导致无药物条件下生长缓慢。
