Vaccinatie proeven (I) Science, 260, 1993, p.1259 <ul><li>Chimpansee gevaccineerd met HIV </li></ul><ul><ul><li>Neutralise...
Vaccinatie proeven (II) <ul><li>Stott </li></ul><ul><ul><li>geïnactiveerd SIV-vaccin </li></ul></ul><ul><ul><li>beschermin...
Adeno-based vaccine aimed at CTL:  the STEP-trial <ul><li>Influence of pre-existing antibodies against vector? </li></ul><...
HIV survives drugs in T cells Balter, Science 278, 1997, 1227; Finzi et al., id. 1295-1300 <ul><li>  </li></ul>Tijd onder ...
Herstel van CD4 na HAART Balter, Science 278, 1997, 1227; Finzi et al., id. 1295-1300 <ul><li>Snel herstel   </li></ul><u...
Active HIV is present in resting T-cells . Identification of a reservoir for HIV-1 in patients on highly active antiretrov...
Is hidden HIV resistant to protease inhibitor?  Finzi  et al. Science 278,1997, 1295 <ul><li>DNA mutation analysis of prot...
Is hidden HIV resistant to protease inhibitor?  Finzi  et al. Science 278,1997, 1295 <ul><li>DNA mutation analysis of prot...
How HIV defeats the immune system Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Paper strong on </li></ul><ul><ul><li>gen...
Time course of HIV-infection Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Immune system clears infection after weeks (de...
How HIV meets the immune system (a)  Nowak & Mc Michael, Sci Am 1995, 42-49
How HIV meets the immune system (b) Nowak & Mc Michael, Sci Am 1995, 42-49
Evolution of HIV: escape mutants Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>For Ab as well as CTL </li></ul><ul><li>In...
Time course of HIV-infection Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Set-point </li></ul><ul><ul><li>Quality of imm...
Model for progression rate Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Importance of conserved epitopes </li></ul><ul><...
Immune dominance  Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>First: strong response </li></ul><ul><ul><li>1-10 MHC-pep...
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GKA deel 2 college 10

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GKA deel 2 college 10

  1. 1. Vaccinatie proeven (I) Science, 260, 1993, p.1259 <ul><li>Chimpansee gevaccineerd met HIV </li></ul><ul><ul><li>Neutraliserende Ab </li></ul></ul><ul><li>Challenge IV (intraveneus) </li></ul><ul><li>Resistentie </li></ul><ul><ul><li>maar: homoloog virus </li></ul></ul><ul><ul><li>challenge op piek Ab-titer </li></ul></ul><ul><ul><li>challenge dosis was laag </li></ul></ul><ul><ul><li>challenge route belangrijk??? </li></ul></ul><ul><ul><ul><li>IV </li></ul></ul></ul><ul><ul><ul><li>mucosaal </li></ul></ul></ul><ul><ul><ul><ul><li>rectaal </li></ul></ul></ul></ul><ul><ul><ul><ul><li>vaginaal </li></ul></ul></ul></ul><ul><ul><li>Door Ab of door..... </li></ul></ul><ul><ul><ul><li>“ Correlate of protection” </li></ul></ul></ul>Science 1993
  2. 2. Vaccinatie proeven (II) <ul><li>Stott </li></ul><ul><ul><li>geïnactiveerd SIV-vaccin </li></ul></ul><ul><ul><li>bescherming in apen tegen SIV, maar ook </li></ul></ul><ul><ul><li>bescherming met controle vaccin, dat geen SIV bevat </li></ul></ul><ul><ul><li>maken apen Ab tegen gastheer eiwitten in envelop van virus? </li></ul></ul><ul><li>Desrosiers </li></ul><ul><ul><li>apen gevaccineerd met geattenueerd SIV </li></ul></ul><ul><ul><li>‘ challenge’ IV met hoge dosis </li></ul></ul><ul><ul><li>protectie (bescherming) </li></ul></ul><ul><ul><li>‘ Correlate’ ??? Onafhankelijk van Ab-titer </li></ul></ul>Science 1993
  3. 3. Adeno-based vaccine aimed at CTL: the STEP-trial <ul><li>Influence of pre-existing antibodies against vector? </li></ul><ul><li>Vaccination increased chance on sero-conversion? </li></ul>Science, 21 Nov 2007  Science 1993
  4. 4. HIV survives drugs in T cells Balter, Science 278, 1997, 1227; Finzi et al., id. 1295-1300 <ul><li> </li></ul>Tijd onder HAART (maanden) Plasma HIV-1 RNA (kopieën/ml 10 2 10 6 10 5 10 4 10 3 10 7 6 12 18 24 30 0 -8 -12
  5. 5. Herstel van CD4 na HAART Balter, Science 278, 1997, 1227; Finzi et al., id. 1295-1300 <ul><li>Snel herstel  </li></ul><ul><li>Latentie is actieve sterfte en geboorte van CD4-cellen </li></ul>
  6. 6. Active HIV is present in resting T-cells . Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therap y, Finzi et al. Science 278,1997, 1295 <ul><li>Resting T-cells (CD4) isolated from HAART-patient </li></ul><ul><li>Supernatant added to T-cells from HIV-minus </li></ul><ul><li> HIV was not measurable in resting cells </li></ul><ul><li> but still present and active </li></ul><ul><li>Cellular half-life! </li></ul><ul><li>p24= amount of capsid protein formed </li></ul>
  7. 7. Is hidden HIV resistant to protease inhibitor? Finzi et al. Science 278,1997, 1295 <ul><li>DNA mutation analysis of protease </li></ul>=========== Ritonavir Saquinavir Patient Protease inhibitor 10 ctcL 20 aagK 33 ttaL 36 atgM 46 atgM 48 gggG 54 atcI 71 gctA 82 gtcV 84 ataI 90 ttg L 1 RTV, SQV --- --- --- --- --- --- --- --- --- --- ---
  8. 8. Is hidden HIV resistant to protease inhibitor? Finzi et al. Science 278,1997, 1295 <ul><li>DNA mutation analysis of protease </li></ul>=========== Answer: No! Ritonavir Saquinavir Patient Protease inhibitor 10 ctcL 20 aagK 33 ttaL 36 atgM 46 atgM 48 gggG 54 atcI 71 gctA 82 gtcV 84 ataI 90 ttg L 1 RTV, SQV --- --- --- --- --- --- --- --- --- --- ---
  9. 9. How HIV defeats the immune system Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Paper strong on </li></ul><ul><ul><li>genetic variation and </li></ul></ul><ul><ul><li>effect on immune system </li></ul></ul><ul><li>Blue spheres: HIV budding from an HIV-infected cell </li></ul>
  10. 10. Time course of HIV-infection Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Immune system clears infection after weeks (decrease viral load by CTL) </li></ul><ul><li>Why not complete clearance? Genetic variation! </li></ul>
  11. 11. How HIV meets the immune system (a) Nowak & Mc Michael, Sci Am 1995, 42-49
  12. 12. How HIV meets the immune system (b) Nowak & Mc Michael, Sci Am 1995, 42-49
  13. 13. Evolution of HIV: escape mutants Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>For Ab as well as CTL </li></ul><ul><li>In beginning: fast replication of fittest variant </li></ul><ul><ul><li>Less genetic variation </li></ul></ul><ul><ul><li>Survival advantage </li></ul></ul><ul><li>Later: less virulent, but many variants (NB: R5 versus X4) </li></ul><ul><li>Fast mutation of HIV due to </li></ul><ul><li>Reverse transcriptase </li></ul><ul><li>Recombination </li></ul><ul><li>APOBEC: Vif </li></ul>
  14. 14. Time course of HIV-infection Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Set-point </li></ul><ul><ul><li>Quality of immune system? </li></ul></ul><ul><li>Diversity break-point </li></ul><ul><ul><li>Too many HIV-variants </li></ul></ul><ul><li>Seroconversion </li></ul>Set-point Diversity break-point
  15. 15. Model for progression rate Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>Importance of conserved epitopes </li></ul><ul><li>Speculative </li></ul>
  16. 16. Immune dominance Nowak & Mc Michael, Sci Am 1995, 42-49 <ul><li>First: strong response </li></ul><ul><ul><li>1-10 MHC-peptides </li></ul></ul><ul><ul><li>Type of MHC important for strength </li></ul></ul><ul><ul><ul><li>MHC B27  no genetic variation </li></ul></ul></ul><ul><ul><ul><li>MHC B8  response to different peptides </li></ul></ul></ul><ul><ul><li>CTL vie for dominance </li></ul></ul><ul><li>Later: response to many epitopes </li></ul><ul><li>Strong response is wrong with fast mutating viruses </li></ul><ul><li> Vaccine: directed against one strong epitope </li></ul>============

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