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HIV protease inhibitors inhibit FACE1/ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy?

Abstract

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.

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  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.

    Source

    Biochemical Society transactions 38:Pt 1 2010 Feb pg 292-6

    MeSH

    Animals
    Antiretroviral Therapy, Highly Active
    HIV Infections
    HIV Protease Inhibitors
    Humans
    Lamin Type A
    Lipodystrophy
    Membrane Proteins
    Metalloendopeptidases
    Mice
    Nuclear Envelope
    Protein Precursors
    Sterol Regulatory Element Binding Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20074077

    Citation

    Goulbourne, Chris N., and David J. Vaux. "HIV Protease Inhibitors Inhibit FACE1/ZMPSTE24: a Mechanism for Acquired Lipodystrophy in Patients On Highly Active Antiretroviral Therapy?" Biochemical Society Transactions, vol. 38, no. Pt 1, 2010, pp. 292-6.
    Goulbourne CN, Vaux DJ. HIV protease inhibitors inhibit FACE1/ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy? Biochem Soc Trans. 2010;38(Pt 1):292-6.
    Goulbourne, C. N., & Vaux, D. J. (2010). HIV protease inhibitors inhibit FACE1/ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy? Biochemical Society Transactions, 38(Pt 1), pp. 292-6. doi:10.1042/BST0380292.
    Goulbourne CN, Vaux DJ. HIV Protease Inhibitors Inhibit FACE1/ZMPSTE24: a Mechanism for Acquired Lipodystrophy in Patients On Highly Active Antiretroviral Therapy. Biochem Soc Trans. 2010;38(Pt 1):292-6. PubMed PMID: 20074077.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - HIV protease inhibitors inhibit FACE1/ZMPSTE24: a mechanism for acquired lipodystrophy in patients on highly active antiretroviral therapy? AU - Goulbourne,Chris N, AU - Vaux,David J, PY - 2010/1/16/entrez PY - 2010/1/16/pubmed PY - 2010/3/17/medline SP - 292 EP - 6 JF - Biochemical Society transactions JO - Biochem. Soc. Trans. VL - 38 IS - Pt 1 N2 - 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. SN - 1470-8752 UR - https://www.unboundmedicine.com/medline/citation/20074077/full_citation L2 - http://www.biochemsoctrans.org/cgi/pmidlookup?view=long&pmid=20074077 DB - PRIME DP - Unbound Medicine ER -