The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product.
The vpr gene of human immunodeficiency virus type 1 (HIV-1) encodes a 15-kDa virion-associated protein that functions as a regulator of cellular processes linked to the HIV life cycle. We report the interaction of a 41-kDa cytosolic viral protein R interacting protein 1 (Rip-1) with Vpr in vitro. Rip-1 displays a wide tissue distribution, including relevant targets of HIV infection. Vpr protein induced nuclear translocation of Rip-1, as did glucocorticoid receptor (GR)-II-stimulating steroids. Importantly, Vpr and Rip-1 coimmunoprecipitated with the human GR as part of an activated receptor complex. Vpr complementation of a vpr mutant virus was also mimicked by GR-II-stimulating steroids. Vpr and GR-II actions were inhibited by mifepristone, a GR-II pathway inhibitor. Together these data directly link the activity of the vpr gene product to the glucocorticoid steroid pathway and provide a biochemical mechanism for the cellular and viral activity of Vpr, as well as suggest that a unique class of antivirals, which includes mifepristone (RU486), may influence HIV-1 replication.
Refaeli
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Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Levy
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Weiner
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D000998:Antiviral Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003432:Cross-Linking Reagents; D003907:Dexamethasone / Q000494:pharmacology; D016336:Gene Products, vpr / Q000235:genetics / Q000378:metabolism*; D005816:Genetic Complementation Test; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008024:Ligands; D015735:Mifepristone / Q000494:pharmacology; D009154:Mutation; D011233:Precipitin Tests; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014158:Transcription, Genetic; D014764:Viral Proteins / Q000302:isolation & purification / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D003432:Cross-Linking Reagents; D016336:Gene Products, vpr; D008024:Ligands; D011965:Receptors, Glucocorticoid; D014764:Viral Proteins; D054325:vpr Gene Products, Human Immunodeficiency Virus; D015735:Mifepristone; D003907:Dexamethasone; D006854:Hydrocortisone