干擾素在HIV 感染與致病中的作用,主要內容,HIV感染與艾滋病-歷史回顧HIV感染導致艾滋病的機制研究艾滋病防制的新進展型干擾素型干擾素在HIV感染中的作用,HIV 感染和艾滋病,艾滋病流行情況及其危害,1981-發現艾滋病,人免疫缺陷病毒（HIV）的發現,Luc Montagnier,Franoise Barr-Sinoussi,Robert Gallo,Lymphadenopathy associated virus(LAV),human T-cell leukemia virus III(HTLV III),LAV,HTLVIII,HTLVIII,HTLVIII與LAV 序列不同,HTLVIII與LAV 序列不同,HTLVIII與LAV 序列高度相似,HTLVIII來源于LAV污染,Robert Gallo 承認,更多數據認為HLTVIII與LAV高度同源,U.S. AND FRANCE END RIFT ON AIDSBy LAWRENCE K. ALTMAN, Special to the New York TimesPublished: April 01, 1987,1987年3月,（網絡圖片，沒把握是否當時場景）,2008年諾貝爾獎-生理與醫學,Luc Montagnier,Franoise Barr-Sinoussi,Robert Gallo,Harald zur Hausen,Human immunodeficiency virus（HIV）,Human immunodeficiency virus（HIV）,HIV病毒的基因和蛋白,HIV的受體和共受體,CCR5CXCR4(coreceptor),T Cells,B cells,Dendritic cells,Natural killer cells,MonocytesMacrophages,Granulocytes,Bone Marrow,Thymus,CD8+ T cells,CD4+ T cells,人免疫細胞的發育和分化,共受體轉換-CCR5 and CXCR4,CCR5Early virusLow pathogenic,CXCR4Late virusHigh pathogenic,HIVCXCR4-原因還是結果,AIDS could develop without CXCR4 virusCCR5 32 patient Low frequency of CXCR4 evolutionCCR5 antagonist treatment Disappearance and re-emerging of CCR5 virus,抗HIV藥物及其作用靶點,臨床上使用的抗病毒藥物,HIV 治療的現狀和未來,Virologic responder,Immune responder,(Functional) Cure,100,80,60,40,20,0,% of total,HIV 干預的目標,HIV 干預的長期目標,HIV感染導致艾滋病的機制,HIV infection and AIDS,HIV感染導致艾滋病的機制,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。Thabo Mbekis denialist policies led to the early deaths of more than 330,000 South Africans,Peter H. Duesberg,研究對象、手段和相關性,臨床隊列,根據疾病進展分期,治療前后各項指標的變化,動物模型,體外實驗,細胞培養，生化實驗,非人靈長類,人源化小鼠,相關性,難度,292390,HIV感染者的發病速度,Long term non-progressor,Elite controller,精英控制者,Nomal progressor,Rapid progressor,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,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),Adapted from (Shultz LD et al. Nat Rev Immunol. 2007. 7:118-30.),HSC,NODSCID,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,2.9,1.2,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 ,CD4/CD8 ratio,No ART,Spleen ,CD4/CD8 ratio,3TC&Stavudine,“” p0.05,Humanized mice for development of novel HIV therapies,廣譜中和性抗體、基因治療、致病機理,不可替代性，HIV, not SIV or SHIV,體積小,優勢：,遺傳背景均一,成本低？,HIV直接感染假說,直接感染？,臨床數據,1、 病人體內大多數死亡的CD4細胞未被感染,2、 不表達CD4細胞也表現為功能異常,直接感染？,Pig tailed macaque,African green monkey,Sootymangabey,mandrill,直接感染？,FIV的受體不是CD4,HIV感染導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感染導致非特異性免疫“活化”，從而導致以CD4免疫缺陷為代表的系統免疫缺陷，最終導致艾滋病的發生。,艾滋病防治新理念、新技術和未來發展方向,早治療的優勢明顯,CD4 200 CD4 350 As early as possible,Drug resistant strains:Development of more drugsBenefit of early treatment : HIV infection is a slow disease衛生經濟學,三個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,早治療和功能性治愈,儲藏庫清除-誘殺（ Shock and Kill ）,骨髓移植與艾滋病治愈,Gero Htter,Timothy Ray Brown),基因治療-CCR5 敲除,骨髓移植與艾滋病治愈,Shift of HIV Tropism in Stem-Cell Transplantation with CCR5 Delta32 Mutation,骨髓移植與艾滋病治愈,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.,廣譜中和性抗體,抗體FC端與免疫反應,廣譜中和性抗體與免疫反應,Cell (2014) 158(5), 989-99.,廣譜中和性抗體的臨床結果,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. Science. 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=0.08Vaccine:Priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV vCP1521) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). Result: Cautious optimism125 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 received the vaccine.,N Engl J Med. 2009 Dec 3;361(23):2209-20,抗原模擬,抗原模擬,HIV感染的致病機理,HIV-1,Quiescent T cells,Activated T cells,Died T cells,提高“免疫不應答患者”免疫重建水平的臨床研究,免疫治療,免疫治療,Science. 2016 Oct 14;354(6309):197-202., 型干擾素,干擾素的發現,1921-1967,1924-2015,Jean Lindenmann,Alick Isaacs,干擾素的分類, 型干擾素, 型干擾素, 型干擾素,IFN-,IFN-,IFN- (12)，,干擾素的受體,IFN-,復雜的干擾素信號通路,pDCs 是天然干擾素產生細胞,干擾素的作用-細胞水平,抗病毒,抑制細胞生長,誘導細胞凋亡, 型干擾素與艾滋病,干擾素在體外抑制HIV復制,J. Virol. 1994, 68(11):7559.,干擾素在體內不能持續抑制SIV復制,Blood. 2012 Jun 14;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. 導致CD4細胞減少,干擾素在體內抑制HIV復制,The Journal of Infectious Diseases 2010; 201(11):16861696,干擾素的免疫病理作用,Acquired Immunodeficiency ？,I型干擾素的異常表達？,pDC activation and HIV pathogenesis,CD4,pDC activation,CD4,pDC activation,Female,Male,Meier, A. et al., Nat Med. 2009. 15, 955.,漿樣樹突狀細胞（pDC）,漿樣樹突狀細胞（pDC）也被稱為干擾素產生細胞,pDCs fro