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  • GKA 2008 a.a.m.thomas@uu.nl

Transcript

  • 1. Deel 2: 70-140
    • Resistentie tegen
      • HIV
      • AIDS
    • HIV receptoren
    • Is elk HIV infectieus?
      • Origin of HIV
      • M- en T-tropisch
    • Infectieroute
    HIV 2008
    • Belangrijke vragen in 1993
      • Medicijnen, werking, HAART
      • Variatie
      • Vaccins
      • Virusreservoir
        • Intracellulair
        • Lymfeknoop
        • In 2004: Darm?
  • 2. In search of AIDS-resistance genes O’Brien & Dean, Scientific American 277, 1997, 28-35
    • LTNP: long-term non-progressors
    • Resistant to HIV? Or to AIDS?
      • Different
    • Around 1980 12000 hemophiliacs received HIV-tainted blood transfusions
      • 10-25% resistant
      • Genetics virus or host?
    HIV 2008
  • 3. Search for genes O’Brien & Dean
    • Two chromosomes  two alleles
      • Hetero- or homozygote
      • Polymorphism:
        • Natural variation
    • Look for genes present in HIV-free and control groups
    • CCR5 allele exclusively present in HIV-free group
      • Why?
      • What is the function of CCR5?
    HIV 2008
  • 4. Binding of HIV to receptor O’Brien & Dean HIV 2008
  • 5. 32 nucleotides deletion prevents expression of CCR5 O’Brien & Dean
    • Defective, truncated receptor CCR5  32 not displayed on membrane
    HIV 2008
  • 6. Adaptation to CXCR4 receptor of T-cell O’Brien & Dean
    • In late stages T- as well as M-tropic virus is expressed
      • No exclusive T-tropic virus present!
    HIV 2008
  • 7. Prevalence of mutant CCR5  32 allele O’Brien & Dean
    • No mutant allele in HIV-infected persons
      • Presence protects against HIV
    • Allele: CCR5  32
      • Lacks 32 nucleotides
    HIV 2008
  • 8. Delayed AIDS progression in heterozygotes O’Brien & Dean
    • Heterozygote
      • 2-3 year difference in untreated persons
    HIV 2008
  • 9. Where does the allele come from? O’Brien & Dean
    • Found predominantly in white persons
    • Not found in African-Americans or East-Asians
    • Migration of humans
    • Due to previous disease?
    HIV 2008
  • 10. Worldwide distribution of allele O’Brien & Dean HIV 2008
  • 11. Co-receptors O’Brien & Dean
    • R5 virus
    • Uses CD4 en CCR5
      • CC= cysteines
      • R=receptor
    • Macrophages, dendritic cells
      • M-tropic virus
    • Slow replication
    • Persistent infection
    • Ligand chemokine:
      • MIP1 
      • MIP1ß
      • RANTES
      • Sends immune cells to infection
    • NSI: non-syncytium-inducing
      • Explanation later
    • X4 virus
    • Uses CD4 en CXCR4
      • Cys-Xaa-Cys
      • R=receptor
    • T helper
      • T-tropic virus
    • Fast replication
    • Lysis
    • Ligand chemokine:
      • SDF-1, stromal derived factor
      • Eotaxine for CCR3
      • Sends immune cells to infection
    • SI: syncytium-inducing
      • Explanation later
    HIV 2008
  • 12. Vaccin virus? Nolan, Cell HIV 2008
  • 13. Resistentie in LTNP O’Brien & Dean
    • Long-term non-progressors: viraal
    • Nef-deletie
      • minder replicatie
    • Vpr
      • R77Q minder apoptose
    • Vpu? Tetherin?
    HIV 2008
    • Long-term non-progressors: cellulair
    • CCR5  32
      • minder infectie
    • MHC-klasse
      • betere immuniteit
    • CD8-specificiteit
      • betere immuniteit
  • 14. MHC-allele factor in set-point
    • Fellay et al., A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1c
      • Science 2007, 317: 5840, 944 - 947
    HIV 2008
    • HLA-C gene
    • Two alleles: T or C
    • HLA-B gene
    • Two alleles: T or G
    Added 091007
  • 15. Follow-up: a microbicide as drug?
    • J. Cohen, Science 306, 2004, 387: Microbicide Shuts the Door on HIV
    • Lederman et al., Science 306, 2004, 485 – 487: Prevention of Vaginal SHIV Transmission in Rhesus Macaques Through Inhibition of CCR5
    • Up till now (Jan 2008) very disappointing results
      • See table at end of handouts…
    HIV 2008 =============