HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through Recipr

HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through Reciprocal Effects on PPAR/GR Co-Regulation

HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through ReciprocalEffects on PPAR/GR Co-RegulationNeeti Agarwal et al.

Sci Transl Med 5, 213ra164 (2013);DOI: 10.1126/scitranslmed.3007148

Editor's Summary

Chewing the Fat with HIV Protein

HIV infection is infamously known for its devastating immunosuppressive effects; however, immunosuppressionis not the whole story. Patients whose viral load is well controlled with antiretroviral therapy (ART) are still at risk for a variety of chronic metabolic complications, including adipose dysfunction. ART drugs have been implicated in some ofthese chronic complications, but others, such as decreased body fat and altered fat distribution, occur in even untreated patients. Now, Agarwal et al. demonstrate that, at least in mice, the HIV protein viral protein R (Vpr) maydirectly contribute to adipose dysfunction.

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The authors began with the observation that Vpr circulates in the blood of HIV-infected patients on ART, even those with no detectable viral load. Paired with the knowledge that Vpr can coactivate the glucocorticoid receptor (GR)and co-repress peroxisome proliferator activated receptor γ (PPARγ), both of which are involved in metabolic

regulation, they hypothesized the Vpr itself may play a pathogenic role in adipose dysfunction in these individuals. They took their studies into two mouse models of Vpr expression that lacked HIV infection: transgenic and

pharmacologic. Vpr alone could disrupt PPAR/GR co-regulation and cell cycle control in adipose depots and liver to produce adipose dysfunction and hepatosteatosis. If these mechanisms hold true in humans, they could lead to

targeted treatment of these metabolic complications with Vpr inhibitors, GR antagonists, or PPARγ/PPARα agonists.

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HIV-1 Vpr Induces Adipose Dysfunction in Vivo Through Reciprocal Effects on PPAR/GR Co-Regulation

HIV

HIV-1VprInducesAdiposeDysfunctioninVivo

ThroughReciprocalEffectsonPPAR/GRCo-Regulation

NeetiAgarwal,1*DinakarIyer,1*SanjeetG.Patel,1 RajagopalV.Sekhar,1,2TerryM.Phillips,3UlrichSchubert,4ToniOplt,1EricD.Buras,1 SusanL.Samson,1,2JacobCouturier,5DorothyE.Lewis,5MariaC.Rodriguez-Barradas,6FarookJahoor,7TomoshigeKino,3JeffreyB.Kopp,8AshokBalasubramanyam1,2§

Viralinfections,suchasHIV,havebeenlinkedtoobesity,butmechanisticevidencethattheycauseadiposedysfunctioninvivoislacking.WeinvestigatedapathogenicrolefortheHIV-1accessoryproteinviralproteinR(Vpr),whichcancoactivatetheglucocorticoidreceptor(GR)andco-repressperoxisomeproliferator–activatedreceptorg(PPARg)invitro,inHIV-associatedadiposedysfunction.VprcirculatedinthebloodofmostHIV-infectedpatientstested,includingthoseonantiretroviraltherapy(ART)withundetectableviralload.Vpr-mediatedmechanismsweredissectedinvivousingmousemodelsexpressingtheVprtransgeneinadiposetissuesandliver(Vpr-Tg)orinfusedwithsyntheticVpr.Bothmodelsdemonstratedacceleratedwhole-bodylipolysis,hyperglycemiaandhypertriglyceridemia,andtissue-specificfindings.Fatdepotsinthesemicehaddiminishedmass,macrophageinfiltration,andbluntedPPARgtargetgeneexpressionbutincreasedGRtargetgeneexpression.Inliver,weobservedbluntedPPARatargetgeneexpression,steatosiswithdecreasedadenosinemonophosphate–activatedproteinkinaseactivity,andinsulinresistance.SimilartohumanHIV-infectedpatients,VprcirculatedintheserumofVpr-Tgmice.Vprblockeddifferentiationinpreadipocytesthroughcellcyclearrest,whereasinmatureadipocytes,itincreasedlipolysiswithreciprocallyalteredassociationofPPARgandGRwiththeirtargetpromoters.Theseresultsdelineateadistinctpathogenicsequence:Vpr,releasedfromHIV-1intissuereservoirsafterART,candisruptPPAR/GRco-regulationandcellcyclecontroltoproduceadiposedysfunctionandhepatosteatosis.Confir-mationofthesemechanismsinHIVpatientscouldleadtotargetedtreatmentofthemetaboliccomplicationswithVprinhibitors,GRantagonists,orPPARg/PPARaagonists.

INTRODUCTION

Viralinfectionsarelinkedtoobesity(1)andfattyliver(2),butevi-dencethattheycauseadiposedysfunctioniscorrelative(3).Invivomechanismswherebyvirusesinduceadipocytedefectsinhumanad-iposedisordershavenotbeenreported.HIVpatientsmanifestadiposedysfunctioncharacterizedbyacceleratedlipolysis,lipoatrophyinsomedepotsandlipohypertrophyinothers,hepatosteatosis,dyslipidemia,insulinresistance,andhyperglycemia.Antiretroviraltherapy(ART)drugshavebeenimplicatedinsomeabnormalities(4).However,adverseeffectsofARTcannotexplainkeyaspectsofthephenotype(5);forexample,hypertriglyceridemiawasnotedbeforetheARTera(6),anddecreasedbodyfat(7),alteredfatdistribution(8),andabnormaladiposegeneexpression(9,10)occurinuntreatedpatients.Thus,HIV-1persecouldca …… 此处隐藏：6458字，全部文档内容请下载后查看。喜欢就下载吧 ……