HIV protease inhibitors inhibit FACE1/ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy?
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.
Goulbourne
Chris N
CN
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Vaux
David J
DJ
D000818:Animals; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects*; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D008060:Lipodystrophy / Q000139:chemically induced* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009685:Nuclear Envelope / Q000378:metabolism / Q000648:ultrastructure; D011498:Protein Precursors / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism
D017320:HIV Protease Inhibitors; D034904:Lamin Type A; D008565:Membrane Proteins; D011498:Protein Precursors; D051779:Sterol Regulatory Element Binding Proteins; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human