Tanaka Tomokazu, Nakazawa Harumasa, Kuriyama Naohide, Kaneki Masao
Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Department of Research, Shriners Hospitals for Children, Boston, MA 02114, USA.
Exp Ther Med. 2018 Feb;15(2):1314-1320. doi: 10.3892/etm.2017.5526. Epub 2017 Nov 17.
Highly active antiretroviral therapy (HAART) has successfully reduced the mortality rate of patients with human immune deficiency virus (HIV) and HIV protease inhibitors (HIV PIs) are key components of HAART. Complications of HAART, particularly those associated with HIV PIs including lipodystrophy and metabolic disturbance, have emerged as an important public health issue. No specific treatment is available to prevent and/or treat HIV PI-associated lipodystrophy and metabolic syndrome. The present study demonstrated that a relatively low-dose of farnesyltransferase inhibitor (FTI), tipifarnib (3 mg/kg/day, subcutaneous injection) and lonafarnib (5 mg/kg/day, subcutaneous injection), prevented the onset of lipodystrophy and metabolic syndrome induced by the combination of two HIV PIs, lopinavir (50 mg/kg/day, intraperitoneal injection) and ritonavir (12.5 mg/kg/day, intraperitoneal injection), in mice. Consistent with previous studies, treatment with lopinavir/ritonavir for 2 weeks decreased body weight, adipose tissue mass, levels of plasma adiponectin and leptin, and increased plasma levels of triglycerides, total cholesterol and insulin. Tipifarnib and lonafarnb prevented or ameliorated all of these alterations in the HIV PI-treated mice. These data identify FTIs as a novel potential strategy to prevent or treat HIV PI-associated lipodystrophy and metabolic syndrome in HIV-infected patients on HAART.
高效抗逆转录病毒疗法（HAART）已成功降低了人类免疫缺陷病毒（HIV）患者的死亡率，而HIV蛋白酶抑制剂（HIV PIs）是HAART的关键组成部分。HAART的并发症，尤其是与HIV PIs相关的并发症，包括脂肪代谢障碍和代谢紊乱，已成为一个重要的公共卫生问题。目前尚无特异性治疗方法可预防和/或治疗与HIV PIs相关的脂肪代谢障碍和代谢综合征。本研究表明，相对低剂量的法尼基转移酶抑制剂（FTI）替匹法尼（3毫克/千克/天，皮下注射）和洛那法尼（5毫克/千克/天，皮下注射）可预防由两种HIV PIs（洛匹那韦（50毫克/千克/天，腹腔注射）和利托那韦（12.5毫克/千克/天，腹腔注射））联合诱导的小鼠脂肪代谢障碍和代谢综合征的发生。与先前的研究一致，用洛匹那韦/利托那韦治疗2周可降低体重、脂肪组织量、血浆脂联素和瘦素水平，并增加血浆甘油三酯、总胆固醇和胰岛素水平。替匹法尼和洛那法尼可预防或改善HIV PI治疗小鼠的所有这些改变。这些数据表明FTIs是预防或治疗接受HAART的HIV感染患者中与HIV PIs相关的脂肪代谢障碍和代谢综合征的一种新的潜在策略。
