Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Biochem Soc Trans. 2010 Feb;38(Pt 1):292-6. doi: 10.1042/BST0380292.
HIV-PIs (HIV protease inhibitors) have proved to be of great benefit for the millions of people suffering from AIDS. However, one of the side effects of this component of combined highly active antiretroviral therapy is lipodystrophy, which affects a large number of the patients taking this class of drug. It has been shown that many of these protease inhibitors inhibit the ZMPSTE24 enzyme responsible for removing the farnesylated tail of prelamin A, which is a nuclear lamina component that has been implicated in some of the nuclear laminopathies. Build up of this protein somehow leads to acquired lipodystrophy, possibly through its interaction with a transcription factor called SREBP-1 (sterol-regulatory-element-binding protein-1). The downstream effect of this is altered fatty acid metabolism and sterol synthesis, which may cause lipodystrophy in patients. The build-up of this protein also appears to have morphological consequences on the nucleus and we reveal, by dual-axis electron tomography, a complex nucleoplasmic reticulum that forms after HIV-PI treatment as a result of acute farnesylated prelamin A accumulation. A greater understanding of the molecular mechanisms leading to lipodystrophy will hopefully facilitate the design of improved HIV-PIs that do not cause this debilitating side effect.
HIV-PIs（HIV 蛋白酶抑制剂）已被证明对数百万艾滋病患者有很大的益处。然而，联合高活性抗逆转录病毒疗法这一成分的一个副作用是脂肪营养不良，这影响了大量服用此类药物的患者。研究表明，许多这些蛋白酶抑制剂抑制 ZMPSTE24 酶，该酶负责去除前层粘连蛋白 A 的法尼基化尾巴，前层粘连蛋白 A 是核纤层的一个组成部分，与一些核纤层蛋白病有关。这种蛋白质的积累会导致获得性脂肪营养不良，可能是通过与一种称为 SREBP-1（固醇调节元件结合蛋白-1）的转录因子相互作用。其下游效应是改变脂肪酸代谢和固醇合成，这可能导致患者出现脂肪营养不良。这种蛋白质的积累似乎也对细胞核有形态学上的影响，我们通过双轴电子断层摄影术揭示，在 HIV-PI 治疗后，由于急性法尼基化前层粘连蛋白 A 的积累，形成了一种复杂的核质网。对导致脂肪营养不良的分子机制的更深入了解，有望促进设计出不会引起这种使人衰弱的副作用的改良型 HIV-PIs。
