Department of Plastic Surgery, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke-Shi, Tochigi, 329-0498, Japan.
Department of Plastic Surgery, University of Tokyo, 7-3-1, Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
AIDS Res Ther. 2022 Mar 4;19(1):14. doi: 10.1186/s12981-022-00432-9.
The authors recently performed plastic surgeries for a small number of patients with hemophilia, HIV infection, and morphologic evidence of lipodystrophy. Because the pathophysiological mechanism of HIV-associated lipodystrophy remains to be elucidated, we analyzed subcutaneous adipose tissues from the patients.
All six patients had previously been treated with older nucleoside analogue reverse-transcriptase inhibitors (NRTIs; stavudine, didanosine or zidovudine). Abdominal and inguinal subcutaneous fat samples were obtained from the HIV+ patients with hemophilia and HIV- healthy volunteers (n = 6 per group), and analyzed via DNA microarray, real-time PCR, flow cytometry and immunohistochemistry.
The time from initial NRTI treatment to collecting samples were 21.7 years in average. Cytometric analysis revealed infiltration of inflammatory M1 macrophages into HIV-infected adipose tissue and depletion of adipose-derived stem cells, possibly due to exhaustion following sustained adipocyte death. Genetic analysis revealed that adipose tissue from HIV+ group had increased immune activation, mitochondrial toxicity, chronic inflammation, progressive fibrosis and adipocyte dysfunction (e.g. insulin resistance, inhibited adipocyte differentiation and accelerated apoptosis). Of note, both triglyceride synthesis and lipolysis were inhibited in adipose tissue from patients with HIV.
Our findings provide important insights into the pathogenesis of HIV-associated lipodystrophy, suggesting that fat redistribution may critically depend on adipocytes' sensitivity to drug-induced mitochondrial toxicity, which may lead either to atrophy or metabolic complications.
作者最近为少数患有血友病、HIV 感染和脂肪营养不良形态学证据的患者进行了整形手术。由于 HIV 相关脂肪营养不良的病理生理机制仍有待阐明，我们分析了这些患者的皮下脂肪组织。
所有 6 名患者此前均接受过较老的核苷类似物逆转录酶抑制剂（NRTIs；司他夫定、地达诺辛或齐多夫定）治疗。从 HIV+血友病患者和 HIV-健康志愿者（每组 6 名）获得腹部和腹股沟皮下脂肪样本，并通过 DNA 微阵列、实时 PCR、流式细胞术和免疫组织化学进行分析。
从首次接受 NRTI 治疗到采集样本的时间平均为 21.7 年。细胞计量分析显示，炎症性 M1 巨噬细胞浸润到 HIV 感染的脂肪组织中，并耗尽脂肪来源的干细胞，可能是由于脂肪细胞持续死亡导致的耗竭。基因分析显示，HIV+组的脂肪组织存在免疫激活增加、线粒体毒性、慢性炎症、进行性纤维化和脂肪细胞功能障碍（例如胰岛素抵抗、脂肪细胞分化抑制和加速凋亡）。值得注意的是，HIV 患者的脂肪组织中甘油三酯合成和脂肪分解均受到抑制。
我们的发现为 HIV 相关脂肪营养不良的发病机制提供了重要的见解，表明脂肪再分布可能严重依赖于脂肪细胞对药物诱导的线粒体毒性的敏感性，这可能导致萎缩或代谢并发症。
