GKA deel 2 college 1

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  • GKA 2009 a.a.m.thomas@uu.nl
  • GKA 2009 a.a.m.thomas@uu.nl
  • GKA 2009 a.a.m.thomas@uu.nl
  • GKA 2009 a.a.m.thomas@uu.nl
  • GKA deel 2 college 1

    1. 2. GKA, 2009-2010 HIV 2009 Deel 2: HIV en AIDS 250 plaatjes Adri Thomas, Kruytgebouw Kamer O503, tel 253 3971 Ontwikkelingsbiologie a.a.m.thomas@uu.nl
    2. 3. Preview-1 <ul><li>Immunology </li></ul><ul><li>Viruses and vaccines </li></ul><ul><li>Epidemiology and Introduction </li></ul><ul><li>Genes and proteins of HIV </li></ul><ul><ul><li>Structural genes </li></ul></ul><ul><ul><li>Replication cycle </li></ul></ul><ul><ul><ul><li>Reverse transcriptase </li></ul></ul></ul><ul><ul><ul><li>Integration </li></ul></ul></ul><ul><li>Topics in 1988 </li></ul><ul><li>Koch postulates </li></ul><ul><li>Host and virus resistence </li></ul><ul><li>Infectivity and porte d éntree </li></ul><ul><ul><li>M- and T-tropic </li></ul></ul><ul><ul><li>Role of dendritic cell </li></ul></ul>HIV 2009 <ul><li>Topics in 1993 </li></ul><ul><ul><li>HAART </li></ul></ul><ul><ul><li>Vaccines </li></ul></ul><ul><li>HIV and the immune systeem </li></ul><ul><ul><li>CD4 </li></ul></ul><ul><ul><li>T-cells </li></ul></ul><ul><li>Topics in 1996 </li></ul><ul><ul><li>HAART </li></ul></ul><ul><ul><li>Therapy </li></ul></ul><ul><li>Epidemiology 2005 </li></ul><ul><li>Vaccines </li></ul><ul><ul><li>B-cell </li></ul></ul><ul><ul><li>T-cell </li></ul></ul><ul><ul><li>Vectors </li></ul></ul><ul><ul><li>Trial 2003 </li></ul></ul><ul><li>Cells, half-life & summary </li></ul>
    3. 4. Contents first part 1-75 HIV 2009 <ul><li>Immunology </li></ul><ul><ul><li>MHC </li></ul></ul><ul><li>Vaccines, viruses </li></ul><ul><li>AIDS/HIV </li></ul><ul><ul><li>Epidemiology </li></ul></ul><ul><ul><li>Replication </li></ul></ul><ul><ul><li>Function genes and proteins </li></ul></ul><ul><ul><li>Is AIDS caused by HIV? </li></ul></ul>Interesting, up-to-date link: http://www.iavireport.org/
    4. 5. Typical course of HIV-infection Science 1996, Pennisi en Cohen <ul><li>Number of T-helpers (CD4 + -cells) decreases after infection </li></ul><ul><li>Viremia is controlled. How? </li></ul>HIV 2009 Viremia: Presence of infectious virus in blood
    5. 6. The immune system HIV 2009 Alberts 4th ed 24.1-2
    6. 7. Immuunsysteem (Engelhard) <ul><li>Witte bloedcellen, lymfocyten </li></ul><ul><ul><li>Monocyte </li></ul></ul><ul><ul><ul><li>Macrofagen (M  ) </li></ul></ul></ul><ul><ul><li>Dendritische cellen (DC) </li></ul></ul><ul><ul><ul><ul><li>Langerhans cellen </li></ul></ul></ul></ul><ul><ul><li>T helper </li></ul></ul><ul><ul><ul><li>T h1 en T h2 </li></ul></ul></ul><ul><ul><li>Cytotoxische T-cel (CTL), T killer </li></ul></ul><ul><ul><li>B-cel </li></ul></ul><ul><ul><ul><li>Expressie en secretie antilichamen </li></ul></ul></ul><ul><li>M  , DC, en B-cel zijn a ntigeen p resenterende c ellen (APC) </li></ul><ul><ul><li>Presenteren peptiden van extracellulaire oorsprong in MHC-II </li></ul></ul><ul><ul><li>Gaan naar lymfeknopen </li></ul></ul><ul><ul><ul><li>Centra van immuuncellen </li></ul></ul></ul><ul><li>Herkenning T-cel van antigeen is sleutel van immuniteit </li></ul>HIV 2009 Alberts 4th ed 24.5
    7. 8. A human lymph node HIV 2009 Alberts 4th ed 24.16-17
    8. 9. A human lymph node HIV 2009 Alberts 4th ed 24.16-17
    9. 10. Humorale immuniteit <ul><li>B-lymfocyt (bursa fabricius) </li></ul><ul><ul><li>Antilichaam (Ab) bindt Ag (antigeen) zoals bacterie, virus in extracellulaire vloeistof </li></ul></ul><ul><ul><li>Binding Ab kan leiden tot </li></ul></ul><ul><ul><ul><li>Inactivatie antigen </li></ul></ul></ul><ul><ul><ul><ul><li>Neutralisatie </li></ul></ul></ul></ul><ul><ul><ul><li>Ag-Ab complex wordt herkend en opgeruimd door </li></ul></ul></ul><ul><ul><ul><ul><li>Complement = cascade van proteolytische enzymen </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Macrofagen: endocytose en proteolyse </li></ul></ul></ul></ul><ul><ul><ul><ul><li>ADCC </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Antibody-dependent cell-mediated cytotoxicity </li></ul></ul></ul></ul></ul>HIV 2009
    10. 11. Humorale immuniteit <ul><li>B-lymfocyt (bursa fabricius) </li></ul><ul><ul><li>Antilichaam (Ab) bindt Ag (antigeen) zoals bacterie, virus in extracellulaire vloeistof </li></ul></ul><ul><ul><li>Binding Ab kan leiden tot </li></ul></ul><ul><ul><ul><li>Inactivatie antigen </li></ul></ul></ul><ul><ul><ul><ul><li>Neutralisatie </li></ul></ul></ul></ul><ul><ul><ul><li>Ag-Ab complex wordt herkend en opgeruimd door </li></ul></ul></ul><ul><ul><ul><ul><li>Complement = cascade van proteolytische enzymen </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Macrofagen: endocytose en proteolyse </li></ul></ul></ul></ul><ul><ul><ul><ul><li>ADCC </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Antibody-dependent cell-mediated cytotoxicity </li></ul></ul></ul></ul></ul>HIV 2009
    11. 12. Cellulaire immuniteit <ul><li>T-lymfocyt (thymus=zwezerik) </li></ul><ul><ul><li>Bestrijdt extra- en intracellulaire Ag </li></ul></ul><ul><ul><li>Bindt aan MHC-I – peptide = antigeen </li></ul></ul><ul><ul><ul><li>M ajor h istocompatibiliteit c omplex </li></ul></ul></ul><ul><ul><ul><li>Op alle cellen met een kern </li></ul></ul></ul><ul><li>Herkenning T-cel van MHC-I – peptide complex </li></ul><ul><ul><li>Peptide uit de cel afkomstig </li></ul></ul><ul><ul><ul><li>Van de cel zelf </li></ul></ul></ul><ul><ul><ul><li>Van virus, bacterie, tumorgen product (?) </li></ul></ul></ul><ul><li>T-cellen scheiden lymfokines uit </li></ul><ul><ul><li>Interleukines, interferon </li></ul></ul><ul><ul><li>Reguleren proliferatie, differentiatie en migratie immuuncellen </li></ul></ul><ul><li>Herkenning T-cel van eigen peptide in MHC </li></ul><ul><ul><li>Auto-immuniteit </li></ul></ul>HIV 2009
    12. 13. Two ways to activate the immune system <ul><li>Lymphokines are hormones or growth factors of the immune system </li></ul><ul><ul><li>Left and right different lymphokines! </li></ul></ul>HIV 2009 B- or T-cell with best fit will proliferate and clonally expand!
    13. 14. Activation of a dendritic cell Hackstein & Thomson Nature Reviews Immunology 4 (2004) 24-35 HIV 2009 Migration Differentiation Antigen uptake Antigen processing in endosome Maturation Migration Functional maturation Bone marrow Draining lymph node MHC-II IL-12 TNF IL-10 T cell Bcell NKcell Mature DC iDC HSC Phenotypically mature DC iDC Antigen
    14. 15. Peptide generation for the MHC Nature 419, 2002, 444-445 <ul><li>MHC: major histocompatibiliteitcomplex or HLA: human leukocyte antigen </li></ul>HIV 2009
    15. 16. Peptide generation for the MHC Nature 419, 2002, 444-445 <ul><li>MHC: major histocompatibiliteitcomplex or HLA: human leukocyte antigen </li></ul>HIV 2009
    16. 17. Activation of T helper <ul><li>Dependent on: </li></ul><ul><ul><li>APC </li></ul></ul><ul><ul><li>Antigen </li></ul></ul><ul><ul><li>MHC </li></ul></ul><ul><ul><li>Environment </li></ul></ul>HIV 2009 Alberts 4th ed 24.47-48
    17. 18. Activation of a CTL and a T helper HIV 2009
    18. 19. Structure of MHC-I and its peptide <ul><li>Heavy chain </li></ul><ul><li>Lighter ß2m microglobulin chain </li></ul><ul><li>Third subunit: peptide of 9 amino acids </li></ul><ul><li>Ends of peptide are held in groove </li></ul>HIV 2009
    19. 20. Structure of MHC-II and peptide <ul><li>alpha subunit </li></ul><ul><li>beta subunit </li></ul><ul><li>3 rd subunit: peptide </li></ul><ul><ul><li>held in middle </li></ul></ul><ul><ul><li>more variable in length </li></ul></ul><ul><ul><li>10-15 amino acids </li></ul></ul>HIV 2009
    20. 21. MHC-I maturation <ul><li>Intracellular proteins </li></ul><ul><ul><li>Viral infections </li></ul></ul><ul><ul><li>Host! (Leader peptides) </li></ul></ul><ul><ul><li>Proteasome </li></ul></ul><ul><li>Transported into ER by TAP (transporter protein) </li></ul><ul><li>Peptide associates with MHC subunits </li></ul><ul><li>To Golgi and plasma membrane </li></ul>HIV 2009
    21. 22. Maturation of MHC-II <ul><li>Two large MHC subunits bind invariant chain </li></ul><ul><li>ER  Golgi </li></ul><ul><li>Invariant chain cleaved to CLIP </li></ul><ul><li>DM replaces CLIP for peptide from endosome </li></ul><ul><li>Contents of endosome are from outside the cell </li></ul>HIV 2009
    22. 23. Summary MHC-I and II <ul><li>All nucleated cells </li></ul><ul><li>Peptide intracellular </li></ul><ul><li>Peptide 8-9 aa </li></ul><ul><ul><li>Binds ends </li></ul></ul><ul><ul><li>Similar aa (R-K, S-T) </li></ul></ul><ul><ul><li>binds during assembly in ER </li></ul></ul><ul><ul><ul><li>Host </li></ul></ul></ul><ul><ul><ul><li>Foreign </li></ul></ul></ul><ul><li>Heavy and small chain </li></ul>HIV 2009 MHC-I
    23. 24. Summary MHC-I and II <ul><li>All nucleated cells </li></ul><ul><li>Peptide intracellular </li></ul><ul><li>Peptide 8-9 aa </li></ul><ul><ul><li>Binds ends </li></ul></ul><ul><ul><li>Similar aa (R-K, S-T) </li></ul></ul><ul><ul><li>binds during assembly in ER </li></ul></ul><ul><ul><ul><li>Host </li></ul></ul></ul><ul><ul><ul><li>Foreign </li></ul></ul></ul><ul><li>Heavy and small chain </li></ul><ul><li>APC </li></ul><ul><ul><li>Antigen-presenting cell </li></ul></ul><ul><ul><ul><li>M  </li></ul></ul></ul><ul><ul><ul><li>DC: Dendritic cell </li></ul></ul></ul><ul><li>Two similar chains </li></ul><ul><li>Peptide 12-15 aa </li></ul><ul><ul><li>Internal binding </li></ul></ul><ul><li>Association with invariant chain </li></ul>HIV 2009 MHC-I MHC-II
    24. 25. Summary MHC-I and II <ul><li>All nucleated cells </li></ul><ul><li>Peptide intracellular </li></ul><ul><li>Peptide 8-9 aa </li></ul><ul><ul><li>Binds ends </li></ul></ul><ul><ul><li>Similar aa (R-K, S-T) </li></ul></ul><ul><ul><li>binds during assembly in ER </li></ul></ul><ul><ul><ul><li>Host </li></ul></ul></ul><ul><ul><ul><li>Foreign </li></ul></ul></ul><ul><li>Heavy and small chain </li></ul><ul><li>APC </li></ul><ul><ul><li>Antigen-presenting cell </li></ul></ul><ul><ul><ul><li>M  </li></ul></ul></ul><ul><ul><ul><li>DC: Dendritic cell </li></ul></ul></ul><ul><li>Two similar chains </li></ul><ul><li>Peptide 12-15 aa </li></ul><ul><ul><li>Internal binding </li></ul></ul><ul><li>Association with invariant chain </li></ul>HIV 2009 <ul><li>Many MHC alleles </li></ul><ul><li>An individual expresses only 3-6 alleles </li></ul>MHC-I MHC-II
    25. 26. Gag-pol eiwit HIV-1 HIV 2009 MGARASVLSGGELDRWEKIRLRPGGKKKYKLKHIVWASRELERFAVNPGLLETSEGCRQILGQLQPSLQT GSEELRSLYNTVATLYCVHQRIEIKDTKEALDKIEEEQNKSKKKAQQAAADTGHSNQVSQNYPIVQNIQG QMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVGGHQAAMQMLKETINEEAA EWDRVHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPT SILDIRQGPKEPFRDYVDRFYKTLRAEQASQEVKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTAC QGVGGPGHKARVLAEAMSQVTNSATIMMQRGNFRNQRKIVKCFNCGKEGHTARNCRAPRKKGCWKCGKEG HQMKDCTERQANFLREDLAFLQGKAREFSSEQTRANSPTRRELQVWGRDNNSPSEAGADRQGTVSFNFPQ VTLWQRPLVTIKIGGQLKEALLDTGADDTVLEEMSLPGRWKPKMIGGIGGFIKVRQYDQILIEICGHKAI GTVLVGPTPVNIIGRNLLTQIGCTLNFPISPIETVPVKLKPGMDGPKVKQWPLTEEKIKALVEICTEMEK EGKISKIGPENPYNTPVFAIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGD AYFSVPLDEDFRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIYQY MDDLYVGSDLEIGQHRTKIEELRQHLLRWGLTTPDKKHQKEPPFLWMGYELHPDKWTVQPIVLPEKDSWT VNDIQKLVGKLNWASQIYPGIKVRQLCKLLRGTKALTEVIPLTEEAELELAENREILKEPVHGVYYDPSK DLIAEIQKQGQGQWTYQIYQEPFKNLKTGKYARMRGAHTNDVKQLTEAVQKITTESIVIWGKTPKFKLPI QKETWETWWTEYWQATWIPEWEFVNTPPLVKLWYQLEKEPIVGAETFYVDGAANRETKLGKAGYVTNRGR QKVVTLTDTTNQKTELQAIYLALQDSGLEVNIVTDSQYALGIIQAQPDQSESELVNQIIEQLIKKEKVYL AWVPAHKGIGGNEQVDKLVSAGIRKVLFLDGIDKAQDEHEKYHSNWRAMASDFNLPPVVAKEIVASCDKC QLKGEAMHGQVDCSPGIWQLDCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTI HTDNGSNFTGATVRAACWWAGIKQEFGIPYNPQSQGVVESMNKELKKIIGQVRDQAEHLKTAVQMAVFIH NFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQNFRVYYRDSRNPLWKGPAKLLWKGEGAVVIQD NSDIKVVPRRKAKIIRDYGKQMAGDDCVASRQDED
    26. 27. Gag-pol eiwit HIV-1 <ul><li>T-cel epitoop TAFTIPSI in protease deel </li></ul>HIV 2009 MGARASVLSGGELDRWEKIRLRPGGKKKYKLKHIVWASRELERFAVNPGLLETSEGCRQILGQLQPSLQT GSEELRSLYNTVATLYCVHQRIEIKDTKEALDKIEEEQNKSKKKAQQAAADTGHSNQVSQNYPIVQNIQG QMVHQAISPRTLNAWVKVVEEKAFSPEVIPMFSALSEGATPQDLNTMLNTVGGHQAAMQMLKETINEEAA EWDRVHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIGWMTNNPPIPVGEIYKRWIILGLNKIVRMYSPT SILDIRQGPKEPFRDYVDRFYKTLRAEQASQEVKNWMTETLLVQNANPDCKTILKALGPAATLEEMMTAC QGVGGPGHKARVLAEAMSQVTNSATIMMQRGNFRNQRKIVKCFNCGKEGHTARNCRAPRKKGCWKCGKEG HQMKDCTERQANFLREDLAFLQGKAREFSSEQTRANSPTRRELQVWGRDNNSPSEAGADRQGTVSFNFPQ VTLWQRPLVTIKIGGQLKEALLDTGADDTVLEEMSLPGRWKPKMIGGIGGFIKVRQYDQILIEICGHKAI GTVLVGPTPVNIIGRNLLTQIGCTLNFPISPIETVPVKLKPGMDGPKVKQWPLTEEKIKALVEICTEMEK EGKISKIGPENPYNTPVFAIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGD AYFSVPLDEDFRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPAIFQSSMTKILEPFRKQNPDIVIYQY MDDLYVGSDLEIGQHRTKIEELRQHLLRWGLTTPDKKHQKEPPFLWMGYELHPDKWTVQPIVLPEKDSWT VNDIQKLVGKLNWASQIYPGIKVRQLCKLLRGTKALTEVIPLTEEAELELAENREILKEPVHGVYYDPSK DLIAEIQKQGQGQWTYQIYQEPFKNLKTGKYARMRGAHTNDVKQLTEAVQKITTESIVIWGKTPKFKLPI QKETWETWWTEYWQATWIPEWEFVNTPPLVKLWYQLEKEPIVGAETFYVDGAANRETKLGKAGYVTNRGR QKVVTLTDTTNQKTELQAIYLALQDSGLEVNIVTDSQYALGIIQAQPDQSESELVNQIIEQLIKKEKVYL AWVPAHKGIGGNEQVDKLVSAGIRKVLFLDGIDKAQDEHEKYHSNWRAMASDFNLPPVVAKEIVASCDKC QLKGEAMHGQVDCSPGIWQLDCTHLEGKVILVAVHVASGYIEAEVIPAETGQETAYFLLKLAGRWPVKTI HTDNGSNFTGATVRAACWWAGIKQEFGIPYNPQSQGVVESMNKELKKIIGQVRDQAEHLKTAVQMAVFIH NFKRKGGIGGYSAGERIVDIIATDIQTKELQKQITKIQNFRVYYRDSRNPLWKGPAKLLWKGEGAVVIQD NSDIKVVPRRKAKIIRDYGKQMAGDDCVASRQDED TAFTIPSI
    27. 28. Antigen and environment determine TH1-TH2 choice HIV 2009 Alberts 4th ed 24.66
    28. 29. Antigen and environment determine TH1-TH2 choice HIV 2009 Alberts 4th ed 24.66
    29. 30. Summary: Immune system activation Silverthorn, Human Physiology HIV 2009
    30. 31. Immuunsysteem activatie Silverthorn, Human Physiology <ul><li>After activation, a small number of memory cells are made </li></ul><ul><ul><li>For B- and T cells </li></ul></ul><ul><ul><li>Speed up immune reaction </li></ul></ul>HIV 2009 ========

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