HIV發(fā)病機(jī)理專(zhuān)題知識(shí)醫(yī)學(xué)課件

HIV發(fā)病機(jī)理專(zhuān)題知識(shí)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第1頁(yè)關(guān)鍵內(nèi)容HIV感染與艾滋病-歷史回顧HIV感染造成艾滋病機(jī)制研究艾滋病防制新進(jìn)展Ⅰ型干擾素Ⅰ型干擾素在HIV感染中作用HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第2頁(yè)HIV感染和艾滋病HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第3頁(yè)艾滋病流行情況及其危害HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第4頁(yè)1981-發(fā)覺(jué)艾滋病HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第5頁(yè)人免疫缺點(diǎn)病毒（HIV）發(fā)覺(jué)LucMontagnierFran?oiseBarré-SinoussiRobertGalloLymphadenopathyassociatedvirus(LAV)humanT-cellleukemiavirusIII(HTLVIII)LAVHTLVIIIHTLVIIIHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第6頁(yè)HTLVIII與LAV序列不一樣HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第7頁(yè)HTLVIII與LAV序列不一樣HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第8頁(yè)HTLVIII與LAV序列高度相同HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第9頁(yè)HTLVIII起源于LAV污染RobertGallo認(rèn)可HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第10頁(yè)更多數(shù)據(jù)認(rèn)為HLTVIII與LAV高度同源HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第11頁(yè)U.S.ANDFRANCEENDRIFTONAIDSByLAWRENCEK.ALTMAN,SpecialtotheNewYorkTimes

Published:April01,19871987年3月（網(wǎng)絡(luò)圖片,沒(méi)把握是否當(dāng)初場(chǎng)景）HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第12頁(yè)諾貝爾獎(jiǎng)-生理與醫(yī)學(xué)LucMontagnierFran?oiseBarré-SinoussiRobertGalloHaraldzurHausenHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第13頁(yè)Humanimmunodeficiencyvirus（HIV）HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第14頁(yè)Humanimmunodeficiencyvirus（HIV）HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第15頁(yè)HIV病毒基因和蛋白HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第16頁(yè)HIV受體和共受體CCR5CXCR4(coreceptor)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第17頁(yè)TCellsB

cellsDendriticcellsNaturalkillercellsMonocytes\MacrophagesGranulocytesBoneMarrowThymusCD8+TcellsCD4+Tcells人免疫細(xì)胞發(fā)育和分化HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第18頁(yè)共受體轉(zhuǎn)換-CCR5andCXCR4CCR5EarlyvirusLowpathogenicCXCR4LatevirusHighpathogenicHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第19頁(yè)HIVCXCR4-原因還是結(jié)果AIDScoulddevelopwithoutCXCR4virusCCR532patientLowfrequencyofCXCR4evolutionCCR5antagonisttreatment

Disappearanceandre-emergingofCCR5virus

HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第20頁(yè)抗HIV藥品及其作用靶點(diǎn)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第21頁(yè)臨床上使用抗病毒藥品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發(fā)病機(jī)理專(zhuān)題知識(shí)第22頁(yè)HIV診療現(xiàn)實(shí)狀況和未來(lái)VirologicresponderImmuneresponder(Functional)Cure100806040200%oftotalHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第23頁(yè)HIV干預(yù)目標(biāo)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第24頁(yè)HIV干預(yù)長(zhǎng)久目標(biāo)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第25頁(yè)HIV感染造成艾滋病機(jī)制HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第26頁(yè)HIVinfectionandAIDSHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第27頁(yè)HIV感染造成艾滋病機(jī)制AIDSHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第28頁(yè)HIVinfectioncauseAIDS!ThaboMbekiIn,SouthAfrica'sPresidentThaboMbekiinvitedseveralHIV/AIDSdenialiststojoinhisPresidentialAIDSAdvisoryPane。。。。。。ThaboMbeki'sdenialistpoliciesledtotheearlydeathsofmorethan330,000SouthAfricansPeterH.DuesbergHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第29頁(yè)研究對(duì)象、手段和相關(guān)性臨床隊(duì)列依據(jù)疾病進(jìn)展分期診療前后各項(xiàng)指標(biāo)改變動(dòng)物模型體外試驗(yàn)細(xì)胞培養(yǎng),生化試驗(yàn)非人靈長(zhǎng)類(lèi)人源化小鼠相關(guān)性難度292390HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第30頁(yè)HIV感染者發(fā)病速度Longtermnon-progressorElitecontroller精英控制者NomalprogressorRapidprogressor長(zhǎng)久不進(jìn)展者進(jìn)展者快速進(jìn)展者HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第31頁(yè)臨床診療與機(jī)制探究抗HIV藥品抑制免疫活化藥品HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第32頁(yè)HIV感染動(dòng)物模型SIV\SHIVHIVFIVHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第33頁(yè)HumanizedmiceWhat?Why?How?MicewithhumanimmunesystemHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第34頁(yè)HistoryofhumanizedmiceNudeSCIDNOD/SCIDNSGRag2-/-1988

199519661983199219981995C

-/-NKTT,BT,BT,BNK,MΦ

HSC

DKOHSCNSGNOD/SCID/C

-/-(NSG)Rag2-/-/C-/-(DKO)Adaptedfrom(ShultzLDetal.NatRevImmunol..7:118-30.)huPBMChuHSCThy/livSCIDHSCNODSCIDT,BNKT,BNK,(MΦ)

DKONewbornmiceHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第35頁(yè)Humanizedmice8-12weeksHSCNewbornmiceBloodhumancellsHumancellsinLymphoidorgansNOT,BorNKcellsHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第36頁(yè)1.Normalmice3.DKO2.humanized123123123SpleenThymusLymphnodesLymphoidorgansinhumanizedmiceHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第37頁(yè)HumanimmunecellsinhuMice2.91.2mDCpDCDCCD11CCD1230.4MonoCD14MΦCD461CD4THTCTLCD8CD4/CD8T6116CD19BTT/B

CD3HumanCD45MouseCD45HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第38頁(yè)HIVinfectionofhumanizedmiceThymusSpleenLymphNodeBMIHC（HIV-P24

antigen）PlasmaViralloadHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第39頁(yè)

HIVinfectionresultedinCD4+TcelllossHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第40頁(yè)Anti-viraldrugsprotectCD4cellsNoARTLymphnodes

CD4/CD8ratioNoARTSpleen

CD4/CD8ratio3TC&Stavudine“”p<0.05HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第41頁(yè)HumanizedmicefordevelopmentofnovelHIVtherapies廣譜中和性抗體、基因診療、致病機(jī)理不可替換性,HIV,notSIVorSHIV體積小優(yōu)勢(shì):遺傳背景均一成本低？HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第42頁(yè)HIV直接感染假說(shuō)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第43頁(yè)直接感染？臨床數(shù)據(jù)1、病人體內(nèi)大多數(shù)死亡CD4細(xì)胞未被感染2、不表示CD4細(xì)胞也表現(xiàn)為功效異常HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第44頁(yè)直接感染？PigtailedmacaqueAfricangreenmonkeyCynomolgusmonkeyRhesusmacaqueSootymangabeymandrillHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第45頁(yè)直接感染？FIV受體不是CD4HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第46頁(yè)HIV感染造成免疫缺點(diǎn)機(jī)制還不清楚以CD4T細(xì)胞降低為代表免疫缺點(diǎn)非特異性免疫活化HLADR+CD38+HIV感染造成非特異性免疫“活化”,從而造成以CD4免疫缺點(diǎn)為代表系統(tǒng)免疫缺點(diǎn),最終造成艾滋病發(fā)生。HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第47頁(yè)艾滋病防治新理念、新技術(shù)和未來(lái)發(fā)展方向HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第48頁(yè)早診療優(yōu)勢(shì)顯著CD4<200→CD4<350→AsearlyaspossibleDrugresistantstrains:DevelopmentofmoredrugsBenefitofearlytreatment:HIVinfectionisaslowdisease衛(wèi)生經(jīng)濟(jì)學(xué)三個(gè)90%HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第49頁(yè)Intensiveantiretroviraltherapyforthefirst18monthsnolongerneedsmedicationsandshowsnosignsofHIV

PediatricHIVspecialistDr.HannahGayUniversityofMississippiMedicalCenter

TheMississippiChild

早診療和功效性治愈HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第50頁(yè)儲(chǔ)藏庫(kù)清除-誘殺（ShockandKill）HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第51頁(yè)骨髓移植與艾滋病治愈GeroHütterTimothyRayBrown)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第52頁(yè)基因診療-CCR5敲除HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第53頁(yè)骨髓移植與艾滋病治愈ShiftofHIVTropisminStem-CellTransplantationwithCCR5Delta32MutationHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第54頁(yè)骨髓移植與艾滋病治愈1234567NEnglJMed.Dec18;371(25):2437-8.HütterG.MoreonshiftofHIVtropisminstem-celltransplantationwithCCR5delta32/delta32mutation.HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第55頁(yè)廣譜中和性抗體HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第56頁(yè)抗體FC端與免疫反應(yīng)HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第57頁(yè)廣譜中和性抗體與免疫反應(yīng)Cell()158(5),989-99.HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第58頁(yè)廣譜中和性抗體臨床結(jié)果HIV-1therapywithmonoclonalantibody3BNC117elicitshostimmuneresponsesagainstHIV-1.Science.May20;352(6288):997-1001.EnhancedclearanceofHIV-1-infectedcellsbybroadlyneutralizingantibodiesagainstHIV-1invivo.Science.May20;352(6288):1001-4.HIV-1antibody3BNC117suppressesviralreboundinhumansduringtreatmentinterruption.Nature.Jul28;535(7613):556-60.HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第59頁(yè)HIVVaccineRV144trail:Thailand(-)p=0.08Vaccine:Priminginjectionsofarecombinantcanarypoxvectorvaccine(ALVAC-HIV[vCP1521])plustwoboosterinjectionsofarecombinantglycoprotein120subunitvaccine(AIDSVAXB/E).Result:Cautiousoptimism125ofthe16,402participantscontractedHIVthroughbehaviorunrelatedtotheirstudyparticipation.Ofthose125,74infectedpersonshadreceivedplaceboand51hadreceivedthevaccine.NEnglJMed.Dec3;361(23):2209-20HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第60頁(yè)抗原模擬HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第61頁(yè)抗原模擬HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第62頁(yè)HIV感染致病機(jī)理HIV-1QuiescentTcellsActivatedTcellsDiedTcellsHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第63頁(yè)藥物適應(yīng)癥臨床實(shí)驗(yàn)#臨床階段靶點(diǎn)主持單位起止時(shí)間Losartan氯沙坦高血壓NCT02049307NCT018529422AGTR2抑制劑UniversityofMinnesota;

NIAID;

MSD2014-2018Dipyridamole雙嘧達(dá)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(lèi)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提升“免疫不應(yīng)答患者”免疫重建水平臨床研究HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第64頁(yè)免疫診療HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第65頁(yè)免疫診療HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第66頁(yè)Science.Oct14;354(6309):197-202.HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第67頁(yè)Ⅰ型干擾素HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第68頁(yè)干擾素發(fā)覺(jué)1921-19671924-JeanLindenmannAlickIsaacsHIV發(fā)病機(jī)理專(zhuān)題知識(shí)第69頁(yè)干擾素分類(lèi)Ⅰ型干擾素Ⅱ型干擾素Ⅲ型干擾素IFN-IFN-IFN-α(12),,,,HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第70頁(yè)干擾素受體IFN-HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第71頁(yè)復(fù)雜干擾素信號(hào)通路HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第72頁(yè)pDCs是天然干擾素產(chǎn)生細(xì)胞HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第73頁(yè)干擾素作用-細(xì)胞水平抗病毒抑制細(xì)胞生長(zhǎng)誘導(dǎo)細(xì)胞凋亡HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第74頁(yè)Ⅰ型干擾素與艾滋病HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第75頁(yè)干擾素在體外抑制HIV復(fù)制J.Virol.1994,68(11):7559.HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第76頁(yè)干擾素在體內(nèi)不能連續(xù)抑制SIV復(fù)制Blood.Jun14;119(24):5750-7.HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第77頁(yè)干擾素對(duì)HIV抑制作用含有亞型特異性HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第78頁(yè)干擾素阻斷和SIV感染Nature()511(7511),601-5.HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第79頁(yè)干擾素診療艾滋病1.不能有效抑制病毒輔助2.造成CD4細(xì)胞降低HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第80頁(yè)干擾素在體內(nèi)抑制HIV復(fù)制TheJournalofInfectiousDiseases;201(11):1686–1696HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第81頁(yè)干擾素免疫病理作用HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第82頁(yè)AcquiredImmunodeficiency？I型干擾素的異常表達(dá)？HIV發(fā)病機(jī)理專(zhuān)題知識(shí)第83頁(yè)pDCactivationandHIVpathogenesisCD4pDCactivationCD4pDCactivationFemaleMaleMeier,A.etal.,NatMed..15,955.HIV發(fā)病機(jī)