Beneficial Effect of TRAIL on HIV Burden, without Detectable Immune Consequences 英文参考文献.docVIP

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Beneficial Effect of TRAIL on HIV Burden, without Detectable Immune Consequences 英文参考文献.doc

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Beneficial Effect of TRAIL on HIV Burden, without Detectable Immune Consequences 英文参考文献

BeneficialEffectofTRAILonHIVBurden,without DetectableImmuneConsequences BrettD.Shepard1,DavideDeForni2,DavidR.McNamara1,AndreaFoli3,StaceyA.Rizza1, RoshiniS.Abraham1,KeithKnutson1,PeterJ.Wettstein1,FrancoLori4,AndrewD.Badley1* 1MayoClinic,Rochester,Minnesota,UnitedStatesofAmerica,2Virostaticss.r.l.,Sassari,Italy,3FondazioneIstitutodiRicoveroeCuraaCarattereScientificoPoliclinico SanMatteo,Pavia,Italy,4ResearchInstituteforGeneticandHumanTherapy,Pavia,Italy Abstract Background: During uncontrolled HIV disease, both TNF-related apoptosis inducing ligand (TRAIL) and TRAIL receptor expressionareincreased.EnhancedTRAILsensitivityisduetoTRAILreceptorup-regulationinducedbygp120.Asaresultof successful antiretroviral therapy TRAIL is down-regulated, and there are fewer TRAIL-sensitive cells. In this setting, we hypothesized that all cells that contain virus, including those productively- and latently-infected, have necessarily been ‘‘primed’’bygp120andremainTRAIL-sensitive,whereasuninfectedcellsremainrelativelyTRAIL-resistant. Methods and Findings: We evaluated the immunologic and antiviral effects of TRAIL in peripheral blood lymphocytes collectedfromHIV-infectedpatientswithsuppressedviralreplication.Theperipheralbloodlymphocytesweretreatedwith recombinant TRAIL or an equivalent amount of bovine serum albumin as a negative control. Treated cells were then analyzedbyquantitativeflowcytometry,ELISPOTforCD4+andCD8+T-cellfunction,andlimitingdilutionmicroculturefor viralburden.Alterationsinthecytokinemilieuoftreatedcellswereassessedwithamultiplexcytokineassay.Treatment withrecombinantTRAILinvitroreducedviralburdeninlymphocytescollectedfromHIV-infectedpatientswithsuppressed viralload.TRAILtreatmentdidnotalterthecytokinemilieuoftreatedcells.Moreover,treatmentwithrecombinantTRAIL hadnoadverseeffectoneitherthequantityorfunctionofimmunecellsfromHIV-infectedpatientswithsuppressedviral replication. Conclusions:TRAILtreatmentmaybeanimportantadjuncttoantiretroviraltherapy,eveninpatientsw