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Human Immunodeficiency Virus (HIV)-1 Viral Protein R Suppresses Transcriptional Activity of Peroxisome Proliferator-Activated Receptor and Inhibits Adipocyte Differentiation: Implications for HIV-Associated Lipodystrophy

Kidney Disease Section (S.S., J.B.K.), National Institute of Diabetes and Digestive and Kidney Diseases; Section on Pediatric Endocrinology (T.K., T.I., G.P.C.), Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development; and Laboratory of Viral Disease (T.C., U.S.), National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; Institute of Virology (U.S.), University of Erlangen, 91054 Erlangen, Germany; Institute of Biochemistry (P.H.), Humboldt University, 10115 Berlin, Germany; and First Department of Pediatrics (G.P.C.), University of Athens, 115 27 Athens, Greece

Address all correspondence and requests for reprints to: Jeffrey B. Kopp, M.D., 10 Center Drive MSC 1268, Bethesda, Maryland 20892-1268. E-mail: jbkopp{at}nih.gov.

HIV-1-infected patients may develop lipodystrophy and insulin resistance. We investigated the effect of the HIV-1 accessory protein viral protein R (Vpr) on the activity of the peroxisome proliferator-activating receptor- (PPAR), a key regulator of adipocyte differentiation and tissue insulin sensitivity. We studied expression of PPAR-responsive reporter genes in 3T3-L1 mouse adipocytes. We investigated Vpr interaction with the PPAR/retinoid X receptor (RXR)-binding site of the c-Cbl-associating protein (CAP) gene using the chromatin immunoprecipitation assay as well as the interaction of Vpr and PPAR using coimmunoprecipitation. Finally, we studied the ability of exogenous Vpr protein to enter cultured adipocytes and retard differentiation. We found that Vpr suppressed PPAR-induced transactivation in both undifferentiated and differentiated 3T3-L1 cells. Transcriptional suppression by Vpr required an intact LXXLL coactivator motif. Vpr suppressed mRNA expression of PPAR-responsive genes in undifferentiated 3T3-L1 cells and associated with the PPAR/RXR-binding site located in the promoter region of the CAP gene. Vpr interacted with the ligand-binding domain of PPAR in an agonist-dependent fashion in vitro. Vpr delivered either by an expression plasmid or as protein added to media suppressed PPAR agonist-induced adipocyte differentiation, assessed as lipid accumulation and mRNA expression of the adipocyte differentiation marker adipocyte P2 in 3T3-L1 cells. In conclusion, circulating Vpr or, alternatively, Vpr produced as a consequence of direct infection of adipocytes could suppress in vivo differentiation of preadipocytes by acting as a corepressor of PPAR-mediated gene transcription. Vpr may alter sensitivity to insulin and thereby contribute to the development of lipodystrophy and insulin resistance observed in HIV-1-infected patients.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ  |  PXR  |  RXRγ

Coregulators:   Vpr  |  p300

Ligands:   Rifampicin  |  GW 9662  |  Dexamethasone  |  Pirinixic acid  |  Mifepristone  |  15-Deoxy-Δ12

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