Gilead Sciences Inc., Foster City, CA, United States of America.
PLoS One. 2020 Feb 28;15(2):e0229617. doi: 10.1371/journal.pone.0229617. eCollection 2020.
An increasing prevalence of overweight and obesity in people living with HIV has been associated with initiation of antiretroviral therapy with integrase strand transfer inhibitors (INSTIs). An off-target inhibition of the endogenous ligand binding to the human melanocortin 4 receptor (MC4R) has been suggested as a potential mechanism for clinical body weight gain following initiation of dolutegravir, an INSTI. In this study, we interrogated several INSTIs for their capacity for antagonism or agonism of MC4R in an in vitro cell-based assays including at concentrations far exceeding plasma concentrations reached at the recommended dosages. Our results indicate that while INSTIs do exhibit the capacity to antagonize MC4R, this occurs at concentrations well above predicted clinical exposure and is thus an implausible explanation for INSTI-associated weight gain.
越来越多的研究表明，接受整合酶抑制剂（INSTIs）治疗的艾滋病毒感染者超重和肥胖的比例在增加。人们认为，在开始使用 dolutegravir（一种 INSTI）后，其对人类黑素皮质素 4 受体（MC4R）内源性配体的非靶点抑制作用是导致临床体重增加的潜在机制。在这项研究中，我们在体外细胞基础测定中检测了几种 INSTIs 对 MC4R 的拮抗或激动作用，包括在远远超过推荐剂量时达到的血浆浓度的浓度下。我们的研究结果表明，尽管 INSTIs 确实具有拮抗 MC4R 的能力，但这种作用发生在远远超过预测临床暴露的浓度下，因此这不是 INSTI 相关体重增加的合理解释。
