hiv发病机理课件

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Ⅰ型干扰素Ⅰ型干扰素在HIV感染中的作用HIV感染和艾滋病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2008年诺贝尔奖-生理与医学LucMontagnierFrançoiseBarré-SinoussiRobertGalloHaraldzurHausenHumanimmunodeficiencyvirus（HIV）Humanimmunodeficiencyvirus（HIV）HIV的受体和共受体

CCR5CXCR4(coreceptor)TCellsB

cellsDendriticcellsNaturalkillercellsMonocytes\MacrophagesGranulocytesBoneMarrowThymusCD8+TcellsCD4+Tcells人免疫细胞的发育和分化共受体转换-CCR5andCXCR4CCR5EarlyvirusLowpathogenicCXCR4LatevirusHighpathogenic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干预的长期目标HIV感染导致艾滋病的机制HIVinfectioncauseAIDS！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-/-19882004199519661983199219981995C

-/-NKTT,BT,BT,BNK,MΦ2005HSC

DKOHSCNSGNOD/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/B

CD3HumanCD45MouseCD45HIVinfectionofhumanizedmiceThymusSpleenLymphNodeBMIHC（HIV-P24

antigen）PlasmaViralload

HIVinfectionresultedinCD4+TcelllossAnti-viraldrugsprotectCD4cellsNoARTLymphnodes

CD4/CD8ratioNoARTSpleen

CD4/CD8ratio3TC&Stavudine“”p<0.05HumanizedmicefordevelopmentofnovelHIVtherapies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CD4<200→CD4<350→AsearlyaspossibleDrugresistantstrains:DevelopmentofmoredrugsBenefitofearlytreatment:HIVinfectionisaslowdisease卫生经济学三个90%Intensiveantiretroviraltherapyforthefirst18monthsnolongerneedsmedicationsandshowsnosignsofHIV

PediatricHIVspecialistDr.HannahGayUniversityofMississippiMedicalCenter

TheMississippiChild

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;

MSD2014-2018Dipyridamole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-1βUCSF2015-2018Vorapaxar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.Ⅰ型干扰素干扰素的发现1921-19671924-2015JeanLindenmannAlickIsaacs干扰素的分类Ⅰ型干扰素Ⅱ型干扰素Ⅲ型干扰素IFN-IFN-IFN-α(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Ⅰ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):1686–1696干扰素的免疫病理作用AcquiredImmunodeficiency？I型干扰素的异常表达？pDCactivationandHIVpathogenesisCD4pDCactivationCD4pDCactivationFemaleMaleMeier,A.etal.,NatMed.2009.15,955.浆样树突状