hiv发病机理

干扰素在HIV感染与致病中的作用主要内容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.Ⅰ型干扰素5.Ⅰ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LucMontagnierFrançoiseBarré-SinoussiRobertGalloLymphadenopathyassociatedvirus(LAV)humanT-cellleukemiavirusIII(HTLVIII)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RobertGallo承认更多数据认为HLTVIII与LAV高度同源U.S.ANDFRANCEENDRIFTONAIDSByLAWRENCEK.ALTMAN,SpecialtotheNewYorkTimesPublished:April01,19871987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LucMontagnierFrançoiseBarré-SinoussiRobertGalloHaraldzurHausenHumanimmunodeficiencyvirus（HIV）Humanimmunodeficiencyvirus（HIV）HIV病毒的基因和蛋白HIV的受体和共受体CCR5CXCR4(coreceptor)TCellsBcellsDendriticcellsNaturalkillercellsMonocytes\MacrophagesGranulocytesBoneMarrowThymusCD8+TcellsCD4+Tcells人免疫细胞的发育和分化共受体转换-CCR5andCXCR4CCR5EarlyvirusLowpathogenicCXCR4LatevirusHighpathogenicHIVCXCR4-原因还是结果AIDScoulddevelopwithoutCXCR4virusCCR532patientLowfrequencyofCXCR4evolutionCCR5antagonisttreatmentDisappearanceandre-emergingofCCR5virus抗HIV药物及其作用靶点临床上使用的抗病毒药物DrugClassGenericName(Acronym)NRTIsAbacavir(ABC),Didanosine(ddl)Emtricitabine(FTC),Lamivudine(3TC)Stavudine(d4T),TenofovirDF(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)FusioninhibitorsEnfuvirtide(T-20)IntegraseRaltegravir(RAL)Elvitegravir(EVG)Dolutegravir(DTG)CCR5inhibitorsMaraviroc(MVC)HIV治疗的现状和未来VirologicresponderImmuneresponder(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HIVinfectionandAIDSHIV感染导致艾滋病的机制AIDSHIVinfectioncauseAIDS！ThaboMbekiIn2000,SouthAfrica'sPresidentThaboMbekiinvitedseveralHIV/AIDSdenialiststojoinhisPresidentialAIDSAdvisoryPane。。。。。。ThaboMbeki'sdenialistpoliciesledtotheearlydeathsofmorethan330,000SouthAfricansPeterH.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Longtermnon-progressorElitecontroller精英控制者NomalprogressorRapidprogressor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SIV\SHIVHIVFIVHumanizedmiceWhat?Why?How?MicewithhumanimmunesystemHistoryofhumanizedmiceNudeSCIDNOD/SCIDNSGRag2-/-19882004199519661983199219981995C-/-NKTT,BT,BT,BNK,MΦ2005HSCDKOHSCNSGNOD/SCID/C-/-(NSG)Rag2-/-/C-/-(DKO)Adaptedfrom(ShultzLDetal.NatRevImmunol.2007.7:118-30.)huPBMChuHSCThy/livSCIDHSCNODSCIDT,BNKT,BNK,(MΦ)2002DKONewbornmiceHumanizedmice8-12weeksHSCNewbornmiceBloodhumancellsHumancellsinLymphoidorgansNOT,BorNKcells1.Normalmice3.DKO2.humanized123123123SpleenThymusLymphnodesLymphoidorgansinhumanizedmiceHumanimmunecellsinhuMice2.91.2mDCpDCDCCD11CCD1230.4MonoCD14MΦCD461CD4THTCTLCD8CD4/CD8T6116CD19BTT/BCD3HumanCD45MouseCD45HIVinfectionofhumanizedmiceThymusSpleenLymphNodeBMIHC（HIV-P24antigen）PlasmaViralloadHIVinfectionresultedinCD4+TcelllossAnti-viraldrugsprotectCD4cellsNoARTLymphnodesCD4/CD8ratioNoARTSpleenCD4/CD8ratio3TC&Stavudine“”p0.05HumanizedmicefordevelopmentofnovelHIVtherapies广谱中和性抗体、基因治疗、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？PigtailedmacaqueAfricangreenmonkeyCynomolgusmonkeyRhesusmacaqueSootymangabeymandrill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CD4200→CD4350→AsearlyaspossibleDrugresistantstrains:DevelopmentofmoredrugsBenefitofearlytreatment:HIVinfectionisaslowdisease卫生经济学三个90%Intensiveantiretroviraltherapyforthefirst18monthsnolongerneedsmedicationsandshowsnosignsofHIVPediatricHIVspecialistDr.HannahGayUniversityofMississippiMedicalCenterTheMississippiChild早治疗和功能性治愈储藏库清除-诱杀（ShockandKill）骨髓移植与艾滋病治愈GeroHütterTimothyRayBrown)基因治疗-CCR5敲除骨髓移植与艾滋病治愈ShiftofHIVTropisminStem-CellTransplantationwithCCR5Delta32Mutation骨髓移植与艾滋病治愈1234567NEnglJMed.2014Dec18;371(25):2437-8.HütterG.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.HIVVaccineRV144trail:Thailand(2003-2006)p=0.08Vaccine:Priminginjectionsofarecombinantcanarypoxvectorvaccine(ALVAC-HIV[vCP1521])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-1QuiescentTcellsActivatedTcellsDiedTcells药物适应症临床实验#临床阶段靶点主持单位起止时间Losartan氯沙坦高血压NCT02049307NCT018529422AGTR2抑制剂UniversityofMinnesota;NIAID;MSD2014-2018Dip