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GKA deel 2 college 5

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GKA deel 2 college 5

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

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