HIV发病机理讲义.ppt

HIV发病机理发病机理主要内容1.HIV感染与艾滋病-历史回顾2.HIV感染导致艾滋病的机制研究3.艾滋病防制的新进展4.型干扰素5.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Luc MontagnierFranoise Barr-SinoussiRobert GalloLymphadenopathy associated virus(LAV)human T-cell leukemia virus III(HTLV III)LAVHTLVIIIHTLVIIIHTLVIII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Robert Gallo 承承认更多数据认为HLTVIII与LAV高度同源U.S.AND FRANCE END RIFT ON AIDSByLAWRENCEK.ALTMAN,SpecialtotheNewYorkTimesPublished:April01,19871987年年3月月（网（网络图片，没把握是否当片，没把握是否当时场景）景）2008年诺贝尔奖-生理与医学Luc MontagnierFranoise Barr-SinoussiRobert GalloHaraldzurHausenHuman immunodeficiency virus（HIV）Human immunodeficiency virus（HIV）HIV病毒的基因和蛋白病毒的基因和蛋白HIV的受体和共受体 CCR5CXCR4(coreceptor)T CellsB cellsDendritic cellsNatural killer cellsMonocytesMacrophagesGranulocytesBone MarrowThymusCD8+T cellsCD4+T cells人免疫细胞的发育和分化共受体转换-CCR5 and CXCR4CCR5Early virusLow pathogenicCXCR4Late virusHigh pathogenicHIVCXCR4-原因还是结果AIDS could develop without CXCR4 virusCCR5 32 patient LowfrequencyofCXCR4evolutionCCR5 antagonist treatment Disappearanceandre-emergingofCCR5virus抗HIV药物及其作用靶点临床上使用的抗病毒药物Drug Class Generic Name(Acronym)NRTIsAbacavir(ABC),Didanosine(ddl)Emtricitabine(FTC),Lamivudine(3TC)Stavudine(d4T),Tenofovir DF(TDF)Zidovudine(ZDV,AZT)NNRTIsDelavirdine(DLV),Efavirenz(EFV)Etravirine(ETR),Nevirapine(NVP)Rilpivirine(RPV)ProteaseInhibitorsAtazanavir(ATV),Darunavir(DRV)Fosamprenavir(FPV),Indinavir(IDV)Nelfinavir(NFV),Ritonavir(RTV)Saquinavir(SQV),Tipranavir(TPV)Fusion inhibitorsEnfuvirtide(T-20)IntegraseRaltegravir(RAL)Elvitegravir(EVG)Dolutegravir(DTG)CCR5 inhibitorsMaraviroc(MVC)HIV 治疗的现状和未来Virologic responderImmune responder(Functional)Cure100806040200%oftotalHIV 干预的目标HIV 干预的长期目标HIV感染导致艾滋病的机制HIV infection and AIDSHIV感染导致艾滋病的机制AIDSHIV infection cause AIDS！Thabo MbekiIn2000,SouthAfricasPresidentThaboMbekiinvitedseveralHIV/AIDSdenialiststojoinhisPresidentialAIDSAdvisoryPane。ThaboMbekisdenialistpoliciesledtotheearlydeathsofmorethan330,000SouthAfricansPeter H.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292390HIV感染者的发病速度Long term non-progressorElite controller精英控制者精英控制者Nomal progressorRapid progressor长期不期不进展者展者进展者展者快速快速进展者展者临床治疗与机制探究抗抗HIV药物物抑制免疫活化的抑制免疫活化的药物物HIV感染的动物模型SIVSHIVHIVFIVHumanized miceWhat?Why?How?Mice with human immune systemHistory of humanized miceNudeSCIDNOD/SCIDNSGRag2-/-19882004199519661983199219981995 C-/-NKTT,BT,BT,B NK,M2005HSC DKOHSCNSGNOD/SCID/C-/-(NSG)Rag2-/-/C-/-(DKO)Adaptedfrom(ShultzLDetal.NatRevImmunol.2007.7:118-30.)huPBMChuHSCThy/livSCIDHSCNODSCIDT,B NKT,B NK,(M)2002DKONew born miceHumanized mice8-12 weeksHSCNew born miceBlood human cellsHuman cells in Lymphoid organsNO T,B or NK cells1.Normal mice3.DKO2.humanized123123123SpleenThymusLymph nodesLymphoid organs in humanized miceHuman immune cells in huMice2.91.2mDCpDCDCCD11CCD1230.4MonoCD14MCD461CD4THTCTLCD8 CD4/CD8 T6116CD19BTT/B CD3Human CD45Mouse CD45HIV infection of humanized miceThymusSpleenLymph NodeBMIHC（HIV-P24 antigen）Plasma Viral load HIV infection resulted in CD4+T cell lossAnti-viral drugs protect CD4 cells No ARTLymph nodes CD4/CD8 ratio No ARTSpleen CD4/CD8 ratio3TC&Stavudine“”p0.05Humanized mice for development of novel HIV therapies广广谱中和性抗体、基因治中和性抗体、基因治疗、致病机理、致病机理不可替代性，HIV,notSIVorSHIV体积小优势：遗传背景均一成本低？HIV直接感染假说直接感染？临床数据床数据1、病人体内大多数死亡的CD4细胞未被感染2、不表达CD4细胞也表现为功能异常直接感染？Pig tailed macaqueAfrican green monkeyCynomolgus monkeyRhesusmacaqueSootymangabeymandrill 直接感染？FIV的受体不是CD4HIV感染导致免疫缺陷的机制还不清楚以CD4T 细胞减少为代表的免疫缺陷非特异性免疫活化HLADR+CD38+HIV感染导致非特异性免疫“活化”，从而导致以CD4免疫缺陷为代表的系统免疫缺陷，最终导致艾滋病的发生。艾滋病防治新理念、新技术和未来发展方向早治疗的优势明显CD4200CD4350AsearlyaspossibleDrug resistant strains:DevelopmentofmoredrugsBenefit of early treatment:HIVinfectionisaslowdisease卫生经济学卫生经济学三个90%Intensiveantiretroviraltherapyforthefirst18monthsnolongerneedsmedicationsandshowsnosignsofHIVPediatricHIVspecialistDr.HannahGayUniversityofMississippiMedicalCenterThe Mississippi Child早治疗和功能性治愈储藏库清除-诱杀（Shock and Kill）骨髓移植与艾滋病治愈GeroHtterTimothyRayBrown)基因治疗-CCR5 敲除骨髓移植与艾滋病治愈Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32 Mutation骨髓移植与艾滋病治愈1234567NEnglJMed.2014Dec18;371(25):2437-8.Htter G.More on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation.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.HIV VaccineRV 144 trail: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感染的致病机理感染的致病机理HIV-1Quiescent T cellsActivated T cellsDied T cells药物药物适应适应症症临床实验临床实验#临床临床阶段阶段靶点靶点主持单位主持单位起止时间起止时间Losartan氯沙坦高血压NCT02049307NCT018529422AGTR2抑制剂UniversityofMinnesota;NIAID;MSD2014-2018Dipyridamole双嘧达莫抗凝血NCT021217562PPDE5抑制剂SharonRiddler;NIAID2014-2017Aspirin阿司匹林抗凝血NCT020816382COX-2抑制剂NIAID2013-2019Clopidogrel氯吡格雷抗凝血NCT025594142P2Y12抑制剂NYU医学院2015-2017Rapamycin雷帕霉素移植排斥NCT024407892mTOR抑制剂AIDSClinicalTrialsGroupNIAID2015-2018Teduglutide替度鲁肽肠炎NCT024313252GLP-2类似物MassachusettsGeneralHospital2015-2019Ruxolitinib鲁索利替尼骨髓纤维化NCT024756552JAK1&JAK2抑制剂2015-2018Metformin二甲双胍糖尿病NCT026593061腺苷酸环化酶抑制剂McGillUniversity2016-2018Canakinumab卡那单抗CAPS综合症NCT022729462IL-1UCSF2015-2018Vorapaxar心梗NCT023947302PAR-1抑制剂KirbyInstituteNIAID；MSD2015-2017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1921-19671924-2015JeanLindenmannAlickIsaacs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.干干扰素素对HIV的抑制作用具有的抑制作用具有亚型特异性型特异性干干扰素阻断和素阻断和SIV感染感染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The Journal of Infectious Diseases 2010;201(11):16861696干扰素的免疫病理作用Acquired Immunodeficiency？I型干扰素的异常表达？pDC activation and HIV pathogenesisCD4pDC activationCD4pDC activationFemaleMaleMeier,A.et al.,Nat Med.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pDCs from huMice are functionalHLA-DR MFI0100200300400MockHIVp=0.02SP04080120160200mockHIVIFNa(pg/ml)HIV infection actives pDCspDC activation&T cell depletionMethods to study function of a gene or cell typeA.Genetically：Knockout,knockdownB.Pharmacological:drug treatmentC.Immunologically：Antibody depletionpDC特异性删除抗体pDC特异性抗体0.04pDCDeplete pDC with specific antibody-Blood0.44IsotypeCD123CD4pDCIsoDeplete pDC with specific antibody-Organs pDCIso pDCIsoThe antibody specifically depletion of pDC pDCIso pDCIso pDCIso pDCIsoT cells(CD3+)B cells(CD19+)mDCs(CD11C+)MonoM(CD14C+)pDC depletion protects human CD4+T cells对照抗体照抗体154BIRNAR进一步抑制非特异性免疫活化一步抑制非特异性免疫活化未感染NonARTHIVIRNARART