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.