hiv發(fā)病機理課件

HIV感染與致病中的作用主要內(nèi)容HIV感染與艾滋病-歷史回顧HIV感染導(dǎo)致艾滋病的機制研究艾滋病防制的新進展Ⅰ型干擾素Ⅰ型干擾素在HIV感染中的作用HIV感染和艾滋病1981-發(fā)現(xiàn)艾滋病人免疫缺陷病毒（HIV）的發(fā)現(xiàn)LucMontagnierFran?oiseBarré-SinoussiRobertGalloLymphadenopathyassociatedvirus(LAV)humanT-cellleukemiavirusIII(HTLVIII)LAVHTLVIIIHTLVIIIHTLVIII與LAV序列不同HTLVIII與LAV序列高度相似HTLVIII來源于LAV污染RobertGallo承認更多數(shù)據(jù)認為HLTVIII與LAV高度同源2008年諾貝爾獎-生理與醫(yī)學(xué)LucMontagnierFran?oiseBarré-SinoussiRobertGalloHaraldzurHausenHumanimmunodeficiencyvirus（HIV）Humanimmunodeficiencyvirus（HIV）HIV的受體和共受體

CCR5CXCR4(coreceptor)TCellsB

cellsDendriticcellsNaturalkillercellsMonocytes\MacrophagesGranulocytesBoneMarrowThymusCD8+TcellsCD4+Tcells人免疫細胞的發(fā)育和分化共受體轉(zhuǎn)換-CCR5andCXCR4CCR5EarlyvirusLowpathogenicCXCR4LatevirusHighpathogenic抗HIV藥物及其作用靶點臨床上使用的抗病毒藥物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治療的現(xiàn)狀和未來VirologicresponderImmuneresponder(Functional)Cure100806040200%oftotalHIV干預(yù)的長期目標(biāo)HIV感染導(dǎo)致艾滋病的機制HIVinfectioncauseAIDS！ThaboMbekiIn2000,SouthAfrica'sPresidentThaboMbekiinvitedseveralHIV/AIDSdenialiststojoinhisPresidentialAIDSAdvisoryPane。。。。。。ThaboMbeki'sdenialistpoliciesledtotheearlydeathsofmorethan330,000SouthAfricansPeterH.Duesberg研究對象、手段和相關(guān)性臨床隊列根據(jù)疾病進展分期治療前后各項指標(biāo)的變化動物模型體外實驗細胞培養(yǎng)，生化實驗非人靈長類人源化小鼠相關(guān)性難度292390HIV感染者的發(fā)病速度Longtermnon-progressorElitecontroller精英控制者NomalprogressorRapidprogressor長期不進展者進展者快速進展者臨床治療與機制探究抗HIV藥物抑制免疫活化的藥物HIV感染的動物模型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

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CD4/CD8ratioNoARTSpleen

CD4/CD8ratio3TC&Stavudine“”p<0.05HumanizedmicefordevelopmentofnovelHIVtherapies廣譜中和性抗體、基因治療、致病機理不可替代性，HIV,notSIVorSHIV體積小優(yōu)勢：遺傳背景均一成本低？HIV直接感染假說直接感染？臨床數(shù)據(jù)1、病人體內(nèi)大多數(shù)死亡的CD4細胞未被感染2、不表達CD4細胞也表現(xiàn)為功能異常直接感染？PigtailedmacaqueAfricangreenmonkeyCynomolgusmonkeyRhesusmacaqueSootymangabeymandrill直接感染？FIV的受體不是CD4HIV感染導(dǎo)致免疫缺陷的機制還不清楚以CD4T細胞減少為代表的免疫缺陷非特異性免疫活化HLADR+CD38+HIV感染導(dǎo)致非特異性免疫“活化”，從而導(dǎo)致以CD4免疫缺陷為代表的系統(tǒng)免疫缺陷，最終導(dǎo)致艾滋病的發(fā)生。艾滋病防治新理念、新技術(shù)和未來發(fā)展方向早治療的優(yōu)勢明顯CD4<200→CD4<350→AsearlyaspossibleDrugresistantstrains:DevelopmentofmoredrugsBenefitofearlytreatment:HIVinfectionisaslowdisease衛(wèi)生經(jīng)濟學(xué)三個90%Intensiveantiretroviraltherapyforthefirst18monthsnolongerneedsmedicationsandshowsnosignsofHIV

PediatricHIVspecialistDr.HannahGayUniversityofMississippiMedicalCenter

TheMississippiChild

早治療和功能性治愈儲藏庫清除-誘殺（ShockandKill）骨髓移植與艾滋病治愈GeroHütterTimothyRayBrown)基因治療-CCR5敲除骨髓移植與艾滋病治愈ShiftofHIVTropisminStem-CellTransplantationwithCCR5Delta32Mutation骨髓移植與艾滋病治愈1234567NEnglJMed.2014Dec18;371(25):2437-8.

HütterG.MoreonshiftofHIVtropisminstem-celltransplantationwithCCR5delta32/delta32mutation.廣譜中和性抗體抗體FC端與免疫反應(yīng)廣譜中和性抗體與免疫反應(yīng)Cell(2014)158(5),989-99.廣譜中和性抗體的臨床結(jié)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抗原模擬抗原模擬HIV感染的致病機理HIV-1QuiescentTcellsActivatedTcellsDiedTcells藥物適應(yīng)癥臨床實驗#臨床階段靶點主持單位起止時間Losartan氯沙坦高血壓NCT02049307NCT018529422AGTR2抑制劑UniversityofMinnesota;

NIAID;

MSD2014-2018Dipyridamole雙嘧達莫抗凝血NCT021217562PPDE5抑制劑SharonRiddler;

NIAID2014-2017Aspirin阿司匹林抗凝血NCT020816382COX-2抑制劑NIAID2013-2019Clopidogrel氯吡格雷抗凝血NCT025594142P2Y12抑制劑NYU醫(yī)學(xué)院2015-2017Rapamycin雷帕霉素移植排斥NCT024407892mTOR抑制劑AIDSClinicalTrialsGroupNIAID2015-2018Teduglutide替度魯肽腸炎NCT024313252GLP-2類似物MassachusettsGeneralHospital2015-2019Ruxolitinib魯索利替尼骨髓纖維化NCT024756552JAK1&JAK2抑制劑2015-2018Metformin二甲雙胍糖尿病NCT026593061腺苷酸環(huán)化酶抑制劑McGillUniversity2016-2018Canakinumab卡那單抗CAPS綜合癥NCT022729462IL-1βUCSF2015-2018Vorapaxar心梗NCT023947302PAR-1抑制劑KirbyInstituteNIAID；MSD2015-2017提高“免疫不應(yīng)答患者”免疫重建水平的臨床研究免疫治療免疫治療Science.2016Oct14;354(6309):197-202.Ⅰ型干擾素干擾素的發(fā)現(xiàn)1921-19671924-2015JeanLindenmannAlickIsaacs干擾素的分類Ⅰ型干擾素Ⅱ型干擾素Ⅲ型干擾素IFN-IFN-IFN-α(12)，，，，干擾素的受體IFN-復(fù)雜的干擾素信號通路pDCs是天然干擾素產(chǎn)生細胞干擾素的作用-細胞水平抗病毒抑制細胞生長誘導(dǎo)細胞凋亡Ⅰ型干擾素與艾滋病干擾素在體外抑制HIV復(fù)制J.Virol.1994,68(11):7559.干擾素在體內(nèi)不能持續(xù)抑制SIV復(fù)制Blood.2012Jun14;119(24):5750-7.干擾素對HIV的抑制作用具有亞型特異性干擾素阻斷和SIV感染

Nature(2014)511(7511),601-5.干擾素治療艾滋病1.不能有效抑制病毒輔助2.導(dǎo)致CD4細胞減少干擾素在體內(nèi)抑制HIV復(fù)制TheJournalofInfectiousDiseases2010;201(11):1686–1696干擾素的免疫病理作用AcquiredImmunodeficiency？I型干擾素的異常表達？pDCactivationandHIVpathogenesisCD4pDCactivationCD4pDCactivationFemaleMaleMeier,A.etal.,NatMed.2009.15,955.漿樣樹突狀