HIVandImmunology

The Immunology of HIV Infection and AIDS,董春升 副教授生物医学研究院2011.12,The Nobel Prize in Physiology or Medicine 2008,Francoise Barr-Sinoussi, The Virology Departement at Institut Pasteur in Paris, FranceLuc Montagnier The World Foundation for AIDS Research and Prevention in Paris, FranceHarald zur Hausen, German Cancer Research Centre in Heidelberg, Germany.,The original descriptions of AIDS, 1981,Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency.Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A.N Engl J Med.1981 Dec 10;305(24):1425-31,An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction.Masur H, Michelis MA, Greene JB, Onorato I, Stouwe RA, Holzman RS, Wormser G, Brettman L, Lange M, Murray HW, Cunningham-Rundles S.N Engl J Med.1981 Dec 10;305(24):1431-8,A new disease,Demographic groups- homosexuals, IV drug abusers, hemophiliacsInfections with opportunistic organismsUnusual cancers- CNS lymphoma, Kaposis sarcoma Decreased CD4+ T cells,Kaposis sarcoma,HIV-1 Virions, Mogtagnier$Gallo,Global summary of the AIDS epidemic, December 2009,Total33.3 million 31.4 35.3 million Adults30.8 million 29.2 32.0 million Women15.9 million 14.8 17.2 million Children under 15 years2.5 million 1.6 3.4 millionTotal2.6 million 2.3 2.8 millionAdults2.2 million 2.0 2.4 millionChildren under 15 years370 000 330 000 410 000Total2.0 million 1.8 2.3 millionAdults1.8 million 1.6 2.1 millionChildren under 15 years270 000 250 000 290 000,Number of people living with HIV in 2009,People newly infected with HIV in 2009,AIDS deaths in 2009,HIV acute and Chronic Disease,Acute infection flu like inlness with fever, weakness, lymphadenopathyLatency-period of years during which infection is active but symptoms are fewChronic disease-diminished CD4+ T cell count contributes to immunodeficiency and secondary infection with opportunistic organisms,Genome structure of HIV-1,HIV Life Cycle (cis infection),Reverse Transcription,Integration,Translation,Assembly/Budding,Maturation,Nuclearimport,HIV Hijacks Dendritic Cells to Facilitate Transmission,Wu and KewalRamani, Nov. 2006,Mechanisms of DC-meditated HIV transmission,Wu and KewalRamani, Nov. 2006,Two-phase model of HIV transfer from DCs to CD4+ T cells,Turville et al. Blood 2004,DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) also known as CD209 (Cluster of Differentiation 209) is a protein which in humans is encoded by the CD209 gene,A C-type of Lectin and has high affinity for ICAM3,Binding with microorganisms by recognizing high-mannose-containing glyucoproteins,such as HIV and HCV,Assay for single-round HIV infection,(iDC, mDCs),Lyse, detect luciferase activity,pVSV-G,N Engl J Med 2009; 360:692-698,Nat Biotechnol. 2010 Aug;28(8):839-47. Human hematopoietic stem/progenitor cells modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo.Holt N, Wang J, Kim K, Friedman G, Wang X, Taupin V, Crooks GM, Kohn DB, Gregory PD, Holmes MC, Cannon PM.SourceKeck School of Medicine of the University of Southern California, Los Angeles, California, USA.AbstractCCR5 is the major HIV-1 co-receptor, and individuals homozygous for a 32-bp deletion in CCR5 are resistant to infection by CCR5-tropic HIV-1. Using engineered zinc-finger nucleases (ZFNs), we disrupted CCR5 in human CD34(+) hematopoietic stem/progenitor cells (HSPCs) at a mean frequency of 17% of the total alleles in a population. This procedure produces both mono- and bi-allelically disrupted cells. ZFN-treated HSPCs retained the ability to engraft NOD/SCID/IL2rgamma(null) mice and gave rise to polyclonal multi-lineage progeny in which CCR5 was permanently disrupted. Control mice receiving untreated HSPCs and challenged with CCR5-tropic HIV-1 showed profound CD4(+) T-cell loss. In contrast, mice transplanted with ZFN-modified HSPCs underwent rapid selection for CCR5(-/-) cells, had significantly lower HIV-1 levels and preserved human cells throughout their tissues. The demonstration that a minority of CCR5(-/-) HSPCs can populate an infected animal with HIV-1-resistant, CCR5(-/-) progeny supports the use of ZFN-modified autologous hematopoietic stem cells as a clinical approach to treating HIV-1.,Generation of HIV-1 Resistant and FunctionalMacrophages From Hematopoietic StemCellderived Induced Pluripotent Stem Cells,Molecular Therapy Nov.2010,Cord BloodCD34+,iPS cell,Oct4, Sox-2, KLF4, c-MYCAnti-HIV combination,OP9,CD133+ HSC,myeloid differentiation,macrophages,The Immune response to HIV,Cytotoxic T cells Antibodies,The changes of viral load, CD4+T, CTL and antibody in HIV infection individual,HIV evade the control of CTL,The latency of HIV infectionThe selection of mutation The loss of CD4+ TcellsPD-1 receptor mediated CTL activity,The low efficiency of neutralizing antibody production,The characteristic of env protein Glycosylation, complexity and three-dimentional conformation2.The mutation of env protein3.The disfunction of B cell,CD4+ T,HIV infection and replication,HIV evasion,pressure,pressure,CTL,Antibody response,induction,induction,assistance,assistance,exhaust,accelerate,+,T cells,The innate immune antiviral cells,TCR restriction expression, CD4-/CD8-Recognition is not dependant on MHCThe,population secrete Th1 cytokines,pDC cells,Bridge of innate and adaptive immune response,Induction of Th1 response,Cellular antiviral factors,TRIM5 and TRIM5-CypA,Tripartite motif protein 5, The family includes 37 members.,The potential mechanisms,1.TRIM5 restricts retroviral infection by specifically recognizing the capsid and promoting its rapid, premature disassembly.,2.rhTRIM5 mediated loss of capsid requires proteasome activity.,APOBEC3G,Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein.Sheehy AM, Gaddis NC, Choi JD, Malim MH.Nature. 2002 Aug 8;418(6898):646-50. DNA deamination mediates innate immunity to retroviral infection.Harris RS Bishop KN Sheehy AM Craig HM Petersen-Mahrt SK Watt IN Neuberger MS Malim MHCell. 2003 Jun 13;113(6):803-9.APOBEC-mediated editing of viral RNABishop KN, Holmes RK, Sheehy AM, Malim MH.Science. 2004 Jul 30;305(5684):645.,APOBEC3G (apoplipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G) is a human enzyme encoded by the APOBEC3G gene that belongs to the APOBEC superfamily of proteins. This family of proteins has been suggested to play an important role in innate anti-viral immunity. APOBEC3G is a cytadine deaminase enzyme and is therefore known as DNA dC-dU-editing enzyme APOBEC-3G and APOBEC-related cytidine deaminase.,Possible mechanism:,1. Cytidine Deamination and Hypermutation,2. Interference with Reverse Transcription,3. Interference with viral DNA integration,J Virol. 2007 July; 81(13): 70997110.,HIV Vif Combat APOBEC3G,Tetherin,Tetherin inhibits retrovirus release and is antagonized by HIV-1 VpuStuart J. D. Neil, Trinity Zang & Paul D. BieniaszNature 451, 425-430 (24 January 2008) | doi:10.1038/nature06553;,Vpu-mediated cell-surface Tetherin down regulation,Highly active anti-retroviral therapy (HARRT),Mortality drop after HARRT,Anti-viral drugs approved by FDA,Protease inhibitors: Saquinavir,Ritonavir, Indinavir, Nelfinavir, Amprenavir, LopinavirFosamprenavir, Atazanavir, Tipranavir, Darunavir,Reverse transcriptase Inhibitors: Zidovudine, Didanosine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Tenofovir,Entry inhibitors: Enfuvirtide(T20), Maraviroc,Integrase inhibitor: Raltegravir,Measuring the latent reservoir,Frequencies of resting CD4+ T cells carrying various forms of HIV-1 DNA,Vaccine strategies,C