HIV 发病机理PPT参考幻灯片

干扰素在HIV感染与致病中的作用,主要内容,HIV感染与艾滋病-历史回顾HIV感染导致艾滋病的机制研究艾滋病防制的新进展型干扰素型干扰素在HIV感染中的作用,HIV感染和艾滋病,艾滋病流行情况及其危害,1981-发现艾滋病,人免疫缺陷病毒（HIV）的发现,LucMontagnier,FranoiseBarr-Sinoussi,RobertGallo,Lymphadenopathyassociatedvirus(LAV),humanT-cellleukemiavirusIII(HTLVIII),LAV,HTLVIII,HTLVIII,HTLVIII与LAV序列不同,HTLVIII与LAV序列不同,HTLVIII与LAV序列高度相似,HTLVIII来源于LAV污染,RobertGallo承认,更多数据认为HLTVIII与LAV高度同源,U.S.ANDFRANCEENDRIFTONAIDSByLAWRENCEK.ALTMAN,SpecialtotheNewYorkTimesPublished:April01,1987,1987年3月,（网络图片，没把握是否当时场景）,2008年诺贝尔奖-生理与医学,LucMontagnier,FranoiseBarr-Sinoussi,RobertGallo,HaraldzurHausen,Humanimmunodeficiencyvirus（HIV）,Humanimmunodeficiencyvirus（HIV）,HIV病毒的基因和蛋白,HIV的受体和共受体,CCR5CXCR4(coreceptor),TCells,Bcells,Dendriticcells,Naturalkillercells,MonocytesMacrophages,Granulocytes,BoneMarrow,Thymus,CD8+Tcells,CD4+Tcells,人免疫细胞的发育和分化,共受体转换-CCR5andCXCR4,CCR5EarlyvirusLowpathogenic,CXCR4LatevirusHighpathogenic,HIVCXCR4-原因还是结果,AIDScoulddevelopwithoutCXCR4virusCCR532patientLowfrequencyofCXCR4evolutionCCR5antagonisttreatmentDisappearanceandre-emergingofCCR5virus,抗HIV药物及其作用靶点,临床上使用的抗病毒药物,HIV治疗的现状和未来,Virologicresponder,Immuneresponder,(Functional)Cure,100,80,60,40,20,0,%oftotal,HIV干预的目标,HIV干预的长期目标,HIV感染导致艾滋病的机制,HIVinfectionandAIDS,HIV感染导致艾滋病的机制,AIDS,HIVinfectioncauseAIDS！,ThaboMbeki,In2000,SouthAfricasPresidentThaboMbekiinvitedseveralHIV/AIDSdenialiststojoinhisPresidentialAIDSAdvisoryPane。ThaboMbekisdenialistpoliciesledtotheearlydeathsofmorethan330,000SouthAfricans,PeterH.Duesberg,研究对象、手段和相关性,临床队列,根据疾病进展分期,治疗前后各项指标的变化,动物模型,体外实验,细胞培养，生化实验,非人灵长类,人源化小鼠,相关性,难度,292390,HIV感染者的发病速度,Longtermnon-progressor,Elitecontroller,精英控制者,Nomalprogressor,Rapidprogressor,长期不进展者,进展者,快速进展者,临床治疗与机制探究,抗HIV药物,抑制免疫活化的药物,HIV感染的动物模型,SIVSHIV,HIV,FIV,Humanizedmice,What?Why?How?,Micewithhumanimmunesystem,Historyofhumanizedmice,Nude,SCID,NOD/SCID,NSG,Rag2-/-,1988,2004,1995,1966,1983,1992,1998,1995,C-/-,NK,T,T,B,T,B,T,BNK,M,2005,NOD/SCID/C-/-(NSG),Rag2-/-/C-/-(DKO),Adaptedfrom(ShultzLDetal.NatRevImmunol.2007.7:118-30.),HSC,NODSCID,T,BNK,T,BNK,(M),2002,DKO,Newbornmice,Humanizedmice,NOT,BorNKcells,1.Normalmice,3.DKO,2.humanized,123,123,123,Spleen,Thymus,Lymphnodes,Lymphoidorgansinhumanizedmice,HumanimmunecellsinhuMice,2.9,1.2,mDC,pDC,DC,CD11C,CD123,0.4,Mono,CD14,M,CD4,61,CD4,TH,TCTL,CD8,CD4/CD8T,61,16,CD19,B,T,T/B,CD3,HumanCD45,MouseCD45,HIVinfectionofhumanizedmice,Thymus,IHC（HIV-P24antigen）,PlasmaViralload,HIVinfectionresultedinCD4+Tcellloss,Anti-viraldrugsprotectCD4cells,NoART,Lymphnodes,CD4/CD8ratio,NoART,Spleen,CD4/CD8ratio,3TC371(25):2437-8.HtterG.MoreonshiftofHIVtropisminstem-celltransplantationwithCCR5delta32/delta32mutation.,广谱中和性抗体,抗体FC端与免疫反应,广谱中和性抗体与免疫反应,Cell(2014)158(5),989-99.,广谱中和性抗体的临床结果,HIV-1therapywithmonoclonalantibody3BNC117elicitshostimmuneresponsesagainstHIV-1.Science.2016May20;352(6288):997-1001.,EnhancedclearanceofHIV-1-infectedcellsbybroadlyneutralizingantibodiesagainstHIV-1invivo.Science.2016May20;352(6288):1001-4.,HIV-1antibody3BNC117suppressesviralreboundinhumansduringtreatmentinterruption.Nature.2016Jul28;535(7613):556-60.,HIVVaccine,RV144trail:Thailand(2003-2006)p=0.08Vaccine:Priminginjectionsofarecombinantcanarypoxvectorvaccine(ALVAC-HIVvCP1521)plustwoboosterinjectionsofarecombinantglycoprotein120subunitvaccine(AIDSVAXB/E).Result:Cautiousoptimism125ofthe16,402participantscontractedHIVthroughbehaviorunrelatedtotheirstudyparticipation.Ofthose125,74infectedpersonshadreceivedplaceboand51hadreceivedthevaccine.,NEnglJMed.2009Dec3;361(23):2209-20,抗原模拟,抗原模拟,HIV感染的致病机理,HIV-1,QuiescentTcells,ActivatedTcells,DiedTcells,提高“免疫不应答患者”免疫重建水平的临床研究,免疫治疗,免疫治疗,Science.2016Oct14;354(6309):197-202.,型干扰素,干扰素的发现,1921-1967,1924-2015,JeanLindenmann,AlickIsaacs,干扰素的分类,型干扰素,型干扰素,型干扰素,IFN-,IFN-,IFN-(12)，,干扰素的受体,IFN-,复杂的干扰素信号通路,pDCs是天然干扰素产生细胞,干扰素的作用-细胞水平,抗病毒,抑制细胞生长,诱导细胞凋亡,型干扰素与艾滋病,干扰素在体外抑制HIV复制,J.Virol.1994,68(11):7559.,干扰素在体内不能持续抑制SIV复制,Blood.2012Jun14;119(24):5750-7.,干扰素对HIV的抑制作用具有亚型特异性,干扰素阻断和SIV感染,Nature(2014)511(7511),601-5.,干扰素治疗艾滋病,1.不能有效抑制病毒辅助,2.导致CD4细胞减少,干扰素在体内抑制HIV复制,TheJournalofInfectiousDiseases2010;201(11):16861696,干扰素的免疫病理作用,AcquiredImmunodeficiency？,I型干扰素的异常表达？,pDCactivationandHIVpathogenesis,CD4,pDCactivation,CD4,pDCactivation,Female,Male,Meier,A.etal.,NatMed.2009.15,955.,浆样树突状细胞（pDC）,浆样树突状细胞（pDC）也被称为干扰素产生细胞,pDCsfromhuMicearefunctional,SP,HIVinfectionactivespDCs,pDCactivation&Tcelldepletion,Methodstostudyfunctionofageneorcelltype,Genetically：Knockout,knockdownPharmacological:drugtreatmentImmunologically：Antibodydepletion,pDC特异性删除抗体,pDC特异性抗体,0.04,pDC,DepletepDCwithspecificantibody-Blood,0.44,Isotype,CD123,CD4,pDC,Iso,DepletepDCwithspecificantibod