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1、干扰素在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 型干扰素 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 Montagnier,Franoise Barr-Sinoussi,Robert Gallo,Lymphadenopathy associated virus (LAV),human T-cell leukemia virus III (HTLV III),LAV,HTLVIII,HTLVIII,HTLVIII与LAV 序
2、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 承认,更多数据认为HLTVIII与LAV高度同源,U.S. AND FRANCE END RIFT ON AIDS By LAWRENCE K. ALTMAN, Special to the New York Times Published: April 01, 1987,1987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,Luc Montagnier,Franoise Barr-Sinoussi,Robert Gallo,Ha
3、rald zur Hausen,Human immunodeficiency virus（HIV）,Human immunodeficiency virus（HIV）,HIV病毒的基因和蛋白,HIV的受体和共受体,CCR5 CXCR4 (coreceptor),T Cells,B cells,Dendritic cells,Natural killer cells,MonocytesMacrophages,Granulocytes,Bone Marrow,Thymus,CD8+ T cells,CD4+ T cells,人免疫细胞的发育和分化,共受体转换-CCR5 and CXCR4,CCR5
4、 Early virus Low pathogenic,CXCR4 Late virus High pathogenic,HIVCXCR4-原因还是结果,AIDS could develop without CXCR4 virus CCR5 32 patient Low frequency of CXCR4 evolution CCR5 antagonist treatment Disappearance and re-emerging of CCR5 virus,抗HIV药物及其作用靶点,临床上使用的抗病毒药物,HIV 治疗的现状和未来,Virologic responder,Immune
5、responder,(Functional) Cure,100,80,60,40,20,0,% of total,HIV 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 AIDS,HIV感染导致艾滋病的机制,AIDS,HIV infection cause AIDS！,Thabo Mbeki,In 2000, South Africas President Thabo Mbeki invited several HIV/AIDS denialists to join his Presidential AIDS Advisory Pane 。
6、Thabo Mbekis denialist policies led to the early deaths of more than 330,000 South Africans,Peter 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,292390,HIV感染者的发病速度,Long term non-progressor,Elite controller,精英控制者,Nomal progressor,Rapid progressor,长期不进展者,进展者,快
7、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,SIVSHIV,HIV,FIV,Humanized mice,What? Why? How?,Mice with human immune system,History of humanized mice,Nude,SCID,NOD/SCID,NSG,Rag2 -/-,1988,2004,1995,1966,1983,1992,1998,1995,C -/-,NK,T,T, B,T, B,T, B NK, M,2005,NOD/SCID /C -/- (NSG),Rag2 -/- /C -/- (DKO),A
8、dapted from (Shultz LD et al. Nat Rev Immunol. 2007. 7:118-30.),HSC,NOD SCID,T, B NK,T, B NK, (M),2002,DKO,New born mice,Humanized mice,NO T, B or NK cells,1. Normal mice,3. DKO,2. humanized,1 2 3,1 2 3,1 2 3,Spleen,Thymus,Lymph nodes,Lymphoid organs in humanized mice,Human immune cells in huMice,2.
9、9,1.2,mDC,pDC,DC,CD11C,CD123,0.4,Mono,CD14,M,CD4,61,CD4,TH,TCTL,CD8,CD4/CD8 T,61,16,CD19,B,T,T/B,CD3,Human CD45,Mouse CD45,HIV infection of humanized mice,Thymus,IHC （HIV-P24 antigen）,Plasma Viral load,HIV infection resulted in CD4+ T cell loss,Anti-viral drugs protect CD4 cells,No ART,Lymph nodes ,
10、CD4/CD8 ratio,No ART,Spleen ,CD4/CD8 ratio,3TC&Stavudine,“” p0.05,Humanized mice for development of novel HIV therapies,广谱中和性抗体、基因治疗、致病机理,不可替代性，HIV, not SIV or SHIV,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？,Pig tailed macaque,African green monkey,Sooty
11、 mangabey,mandrill,直接感染？,FIV的受体不是CD4,HIV感染导致免疫缺陷的机制还不清楚,以CD4 T 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 As early as possible,Drug resistant strains: Development of more drugs Benefit of early treatment : HIV
12、 infection is a slow disease 卫生经济学,三个90%,Intensive antiretroviral therapy for the first 18 months no longer needs medications and shows no signs of HIV,Pediatric HIV specialist Dr. Hannah Gay University of Mississippi Medical Center,The 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
13、病治愈,Gero Htter,Timothy Ray Brown),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,N Engl J Med. 2014 Dec 18;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
14、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-1 therapy with monoclonal antibody 3BNC117 elicits host immune responses against HIV-1. Science. 2016 May 20;352(6288):997-1001.,Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Sc
15、ience. 2016 May 20;352(6288):1001-4.,HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 2016 Jul 28;535(7613):556-60.,HIV Vaccine,RV 144 trail: Thailand ( 2003-2006) p=0.08 Vaccine: Priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV
16、vCP1521) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). Result: Cautious optimism 125 of the 16,402 participants contracted HIV through behavior unrelated to their study participation. Of those 125, 74 infected persons had received placebo and 51 had rec
17、eived the vaccine.,N Engl J Med. 2009 Dec 3;361(23):2209-20,抗原模拟,抗原模拟,HIV感染的致病机理,HIV-1,Quiescent T cells,Activated T cells,Died T cells,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. 2016 Oct 14;354(6309):197-202., 型干扰素,干扰素的发现,1921-1967,1924-2015,Jean Lindenmann,Alick Isaacs,干扰素的分类, 型干扰素, 型干扰素, 型干扰素,IFN-
18、,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. 2012 Jun 14;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
19、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 pathogenesis,CD4,pDC activation,CD4,pDC activation,Female,Male,Meier, 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 a
20、re functional,SP,HIV infection actives pDCs,pDC activation & T cell depletion,Methods to study function of a gene or cell type,Genetically：Knockout, knockdown Pharmacological: drug treatment Immunologically： Antibody depletion,pDC特异性删除抗体,pDC特异性抗体,0.04,pDC,Deplete pDC with specific antibody-Blood,0.4
21、4,Isotype,CD123,CD4,pDC,Iso,Deplete pDC with specific antibody-Organs, pDC,Iso, pDC,Iso,The antibody specifically depletion of pDC, pDC,Iso, pDC,Iso, pDC,Iso, pDC,Iso,T cells (CD3+),B cells (CD19+),mDCs (CD11C+),MonoM (CD14C+),pDC depletion protects human CD4+ T cells,对照抗体,154B,IRNAR进一步抑制非特异性免疫活化,未感染,Non,ART,HIV,IRNAR,ART,