Sorbonne Université, Inserm Unité Mixte de Recherche S938, Centre de Recherche Saint-Antoine, Institut Hospitalo-Universitaire de Cardio-Métabolisme et Nutrition, Paris, France.
Commissariat à l'Energie Atomique, Université Paris Sud 11, Inserm U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, Infectious Disease Models and Innovative Therapies Department, Fontenay-aux-Roses, France.
Clin Infect Dis. 2020 Dec 17;71(10):e549-e560. doi: 10.1093/cid/ciaa259.
Although some integrase strand transfer inhibitors (INSTIs) promote peripheral and central adipose tissue/weight gain in people with human immunodeficiency virus (PHIV), the underlying mechanism has not been identified. Here, we used human and simian models to assess the impact of INSTIs on adipose tissue phenotype and function.
Adipocyte size and fibrosis were determined in biopsies of subcutaneous and visceral adipose tissue (SCAT and VAT, respectively) from 14 noninfected macaques and 19 PHIV treated or not treated with an INSTI. Fibrosis, adipogenesis, oxidative stress, mitochondrial function, and insulin sensitivity were assessed in human proliferating or adipocyte-differentiated adipose stem cells after long-term exposure to dolutegravir or raltegravir.
We observed elevated fibrosis, adipocyte size, and adipogenic marker expression in SCAT and VAT from INSTI-treated noninfected macaques. Adiponectin expression was low in SCAT. Accordingly, SCAT and VAT samples from INSTI-exposed patients displayed higher levels of fibrosis than those from nonexposed patients. In vitro, dolutegravir and, to a lesser extent, raltegravir were associated with greater extracellular matrix production and lipid accumulation in adipose stem cells and/or adipocytes as observed in vivo. Despite the INSTIs' proadipogenic and prolipogenic effects, these drugs promoted oxidative stress, mitochondrial dysfunction, and insulin resistance.
Dolutegravir and raltegravir can directly impact adipocytes and adipose tissue. These INSTIs induced adipogenesis, lipogenesis, oxidative stress, fibrosis, and insulin resistance. The present study is the first to shed light on the fat modifications observed in INSTI-treated PHIV.
尽管一些整合酶链转移抑制剂（INSTIs）会导致人类免疫缺陷病毒（PHIV）感染者出现外周和中枢性脂肪组织/体重增加，但其中的机制尚未明确。在此，我们使用人类和灵长类动物模型来评估 INSTIs 对脂肪组织表型和功能的影响。
对 14 只非感染恒河猴的皮下和内脏脂肪组织（SCAT 和 VAT）活检样本进行脂肪细胞大小和纤维化检测，其中 19 只 PHIV 感染者接受或未接受 INSTI 治疗。在长期暴露于度鲁特韦或拉替拉韦后，评估人增殖或脂肪细胞分化的脂肪干细胞中的纤维化、脂肪生成、氧化应激、线粒体功能和胰岛素敏感性。
我们观察到接受 INSTI 治疗的非感染恒河猴的 SCAT 和 VAT 中纤维化、脂肪细胞大小和脂肪生成标志物表达升高。SCAT 中的脂联素表达较低。因此，与未暴露于 INSTI 的患者相比，暴露于 INSTI 的患者的 SCAT 和 VAT 样本显示出更高的纤维化水平。在体外，度鲁特韦，并且在较小程度上，拉替拉韦与脂肪干细胞和/或脂肪细胞中更多的细胞外基质产生和脂质积累相关，这与体内观察到的结果一致。尽管 INSTIs 具有促脂肪生成和促脂生成作用，但这些药物促进了氧化应激、线粒体功能障碍和胰岛素抵抗。
度鲁特韦和拉替拉韦可直接影响脂肪细胞和脂肪组织。这些 INSTIs 诱导了脂肪生成、脂肪生成、氧化应激、纤维化和胰岛素抵抗。本研究首次阐明了在 INSTI 治疗的 PHIV 中观察到的脂肪改变。
